Bicyclo[3.2.1]octyl amide derivatives and uses of same

ABSTRACT

The present invention provides bicyclo[3.2.1]octyl amide derivatives of formula (I): 
     
       
         
         
             
             
         
       
     
     wherein L, R 1  and R 2  are as defined herein, or a pharmaceutically acceptable salt thereof; and pharmaceutical compositions and methods using the same.

FIELD OF THE INVENTION

The present invention provides bicyclo[3.2.1]octyl amide derivatives, aswell as pharmaceutical compositions and methods of treatment using same.

BACKGROUND OF THE INVENTION

This invention concerns bicyclo[3.2.1]octyl amide derivatives, which actas allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5receptors or mGluR5), as well as pharmaceutical compositions and methodsof treatment utilizing these compounds.

Glutamate is the major excitatory neurotransmitter in the mammaliancentral nervous system. One means of modulating glutamateneurotransmission is through metabotropic glutamate receptors (mGluRs);another means being ionotropic receptors. Presently, eight mGluRs havebeen cloned and classified into three groups based on sequence homology,preferred signal transduction pathway and pharmacology. Group I ofmGluRs includes mGluR1 and mGluR5, while Group II comprises mGluR2 andmGluR3 and Group III comprises mGlu4, 6, 7 and 8 receptors.

mGlu receptors have an essential role in normal brain functions, as wellas in neurological, psychiatric, and neuromuscular disorders. mGlu5receptors are located primarily postsynaptically and highly expressed inthe limbic brain regions. mGlu5 receptors also are expressed in thethalamus, spinal cord, and vagal nerve systems, as well as peripherallyin the skin on nerve endings and C fibers.

Ligands to the mGlu5 receptors have been shown to have promise forperipheral and central nervous system disorders. See e.g., G. Jaeschkeet al., “mGlu5 receptor antagonists and their therapeutic potential,”Expert Opin. Ther. Patents, 2008, 18, 2: 123-142. Yet some proffer thatglutamate analogs targeting the orthosteric binding site may be limitedby low brain penetration and insufficient selectivity with respect tothe different mGluRs subtypes. Synthetic agonists may lead to continuousstimulation of the receptor since they are often designed to bemetabolically stable. This continuous stimulation is not necessarilydesirable, due to potential receptor desensitization issues. Also, withrespect to receptor occupancy, synthetic antagonists may lead toprolonged blockade of receptor function, which may not be compatiblewith the kinetics of the pathology of a central nervous system disorder.

However, a more selective and controlled “fine-tuning” action on themGlu5 receptor is feasible through allosteric modulation. See e.g., P.Bach et al., “Metabotropic glutamate receptor 5 modulators and theirpotential therapeutic applications,” Expert Opin. Ther. Patents, 2007,17, 4: 371-381. Allosteric modulation refers to binding by a modulatorligand to a site on a receptor that is different from the orthostericprimary substrate or ligand binding site. This ligand binding processresults in conformational changes, which may profoundly influence thefunction of the protein (e.g., G protein-coupled receptors such asmGluRs, including mGluR5). Novel mGluR5 ligands that allostericallymodulate the mGlu5 receptor may improve the therapeutic window oftraditional central nervous system agents and/or the treatment ofcentral nervous system disorders. The present invention is directedthese, and other important, ends.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula (I):

wherein:

-   -   L is —NHCO— or —CONH—; and    -   R¹ and R² are each independently alkyl, cycloalkyl,        ketocycloalkyl, heterocyclyl, aryl or heteroaryl, which is        optionally mono-, di-, or tri-substituted independently with        alkyl, alkoxy, halogen, cyano, nitro, trifluoroalkyl, amino,        alkylamino, dialkylamino, acyl, aryl, heteroaryl, heterocyclyl,        heterocyclyl-R³, —NHR³, —N(alkyl)R³, —C(O)NHR³, —C(O)N(alkyl)R³,        —NHC(O)R³, —N(alkyl)C(O)R³, —OH or —OR³, wherein:        -   R³ is C₁-C₆alkyl or C₁-C₆cycloalkyl, which is optionally            substituted with halogen, —CN, —NH₂, —NH(C₁-C₃alkyl),            —N(C₁-C₃alkyl)₂, C₁-C₃alkylheterocyclyl,            C₁-C₃alkylcarbamate, —C(O)NH(C₁-C₃alkyl),            —C(O)N(C₁-C₃alkyl)₂, —NHC(O)—C₁-C₃alkyl,            —N(C₁-C₃alkyl)-C(O)—C₁-C₃alkyl, OH, or —O—C₁-C₆alkyl; or            a pharmaceutically acceptable salt thereof.

The present invention also provides a pharmaceutical compositioncomprising at least one compound of the invention or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier.

The present invention also provides a method of treating a disease ordisorder, the method comprises administering a therapeutically effectiveamount of at least one compound of the present invention or apharmaceutically acceptable salt thereof to a mammal in need thereof,wherein the disease or disorder is a central nervous system disease ordisorder. In some embodiments of the method, a symptom of the disease ordisorder is treated.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the present invention provides bicyclo[3.2.1]octyl amidederivatives. The present invention comprises a compound of formula (I-A)or (I-B):

wherein:

-   -   R¹ and R² are each independently alkyl, cycloalkyl,        ketocycloalkyl, heterocyclyl, aryl or heteroaryl, which is        optionally mono-, di-, or tri-substituted independently with        alkyl, alkoxy, halogen, cyano, nitro, trifluoroalkyl, amino,        alkylamino, dialkylamino, acyl, aryl, heteroaryl, heterocyclyl,        heterocyclyl-R³, —NHR³, —N(alkyl)R³, —C(O)NHR³, —C(O)N(alkyl)R³,        —NHC(O)R³, —N(alkyl)C(O)R³, —OH or —OR³, wherein:        -   R³ is C₁-C₆alkyl or C₁-C₆cycloalkyl, which is optionally            substituted with halogen, —CN, —NH(C₁-C₃alkyl),            —N(C₁-C₃alkyl)₂, C₁-C₃alkylheterocyclyl,            C₁-C₃alkylcarbamate, —C(O)NH(C₁-C₃alkyl),            —C(O)N(C₁-C₃alkyl)₂, —NHC(O)—C₁-C₃alkyl,            —N(C₁-C₃alkyl)-C(O)—C₁-C₃alkyl, OH, or —O—C₁-C₆alkyl; or            a pharmaceutically acceptable salt thereof.

The term “alkyl”, employed alone or as part of a group, is definedherein, unless otherwise stated, as either a straight-chain or branchedsaturated hydrocarbon of 1 to 8 carbon atoms. In some embodiments, thealkyl moiety contains 8, 7, 6, 5, 4, 3, 2 or 1 carbon atoms. Where theterm “alkyl” appears herein without a carbon atom range it means a rangeof C₁-C₈. Examples of saturated hydrocarbon alkyl moieties include, butare not limited to, chemical groups such as methyl, ethyl, n-propyl,isopropyl, n-butyl, tert-butyl, iso-butyl, sec-butyl, n-pentyl, n-hexyl,and the like.

The term “alkoxy”, employed alone or in combination with other terms, isdefined herein, unless otherwise stated, as —O-alkyl, where “alkyl” isas previously defined herein. Examples of alkoxy moieties include, butare not limited to, chemical groups such as methoxy, ethoxy,iso-propoxy, sec-butoxy, tert-butoxy, and homologs, isomers, and thelike. Alkoxy also refers to —O-alkyl moieties where the alkyl group issubstituted by hydroxy, cyano, alkoxy, alkylamino, dialkylamino,alkylamide, dialkylamide, and the like, including without limitation,—OC₁-C₄alkyl-OH, —OC₁-C₄alkyl-OCH₃, —OC₁-C₄alkyl-NHCH₃,—OC₁-C₄alkyl-N(CH₃)₂, —OC₁-C₄alkyl-CONHCH₃, —OC₁-C₄alkyl-CON(CH₃)₂,—OC₁-C₄alkyl-NHCOCH₃, and —OC₁-C₄alkyl-N(CH₃)COCH₃.

As used herein, the term “cycloalkyl”, employed alone or in combinationwith other terms, is defined herein, unless otherwise stated, as acyclized alkyl group having from 3 to 8 ring carbon atoms, where “alkyl”is as defined herein. Examples of cycloalkyl moieties include, but arenot limited to, chemical groups such as cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl.

As used herein, the term “ketocycloalkyl”, employed alone or incombination with other terms, is defined herein, unless otherwisestated, as a cycloalkyl having a keto radical attached thereto, where“cycloalkyl” is as defined herein. Examples include cyclopentanone orcyclohexanone.

The terms “halo” or “halogen”, employed alone or in combination withother terms, is defined herein, unless otherwise stated, as fluoro,chloro, bromo, or iodo.

The term “aryl”, employed alone or in combination with other terms, isdefined herein, unless otherwise stated, as an aromatic hydrocarbon ofup to 14 carbon atoms, which can be a single ring (monocyclic) ormultiple rings (e.g., bicyclic, tricyclic, polycyclic) fused together orlinked covalently. Any suitable ring position of the aryl moiety can becovalently linked to the defined chemical structure. Examples of arylmoieties include, but are not limited to, chemical groups such asphenyl, benzyl, 1-naphthyl, 2-naphthyl, and the like. An aryl group canbe unsubstituted or substituted as described herein.

The term “heteroaryl” employed alone or in combination with other terms,is defined herein, unless otherwise stated, as a monocyclic orpolycyclic (fused together or linked covalently) aromatic hydrocarbonring comprising one or more heteroatoms independently selected fromnitrogen, oxygen, and sulfur. A heteroaryl group comprises up to 14carbon atoms and 1 to 6 heteroatoms. Examples of heteroaryl groupsinclude, but are not limited to, pyridinyl, pyridazinyl, triazinyl,pyrrolyl, pyrazolyl, imidazolyl, (1,2,3,)- and (1,2,4)-triazolyl,pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thienyl, isoxazolyl,thiazolyl, oxazolyl, 2-quinolinyl, 2-quinazolinyl, 3-phenyl-2-quinolinyland the like. A heteroaryl group can be unsubstituted or substituted asdescribed herein.

The term “heterocyclyl” employed alone or in combination with otherterms, is defined herein, unless otherwise stated, as a univalent groupformed by removing a hydrogen atom from any ring atom of a heterocycle.

The term “acyl” employed alone or in combination with other terms, isdefined herein, unless otherwise stated, as groups of formula—C(O)-alkyl, where alkyl is a previously described herein; i.e., analkylcarbonyl, such as formyl, acetyl and the like.

The term “aminoalkyl” employed alone or in combination with other terms,is defined herein, unless otherwise stated, as alkyl-amino, where theterm “alkyl” is as previously defined herein and the term “amino” is—NH₂, —NH—, or —N<. Non-limiting examples include —CH₃NH— and CH₃CH₂NH—.

The term “alkylamino” employed alone or in combination with other terms,is defined herein, unless otherwise stated, as amino-alkyl, where theterm “alkyl” is as previously defined herein and the term “amino” is—NH₂, —NH—, or —N<. Non-limiting examples include —NHCH₃ and —NHCH₂CH₃.

In some embodiments of the invention, R¹ and R² are both aryl. In someembodiments, R¹ and R² are both heteroaryl. In some embodiments, R¹ isaryl and R² is heteroaryl. In some embodiments, either R¹ or R² isheteroaryl. In some embodiments, either R¹ or R² is aryl.

In some embodiments of the invention, at least one aryl is phenyl. Insome embodiments, at least one heteroaryl is benzofuranyl,benzo[c]isoxazolyl, benzooxazolyl, benzothiazolyl,dihydrothieno[3,4-b][1,4]dioxinyl, furanyl, imidazo[1,2-a]pyridinyl,indazolyl, indolinyl, indolyl, isoquinolinyl, isoxazolyl,naphthyridinyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl,pyrimidinyl, pyrrolo[3,2-c]pyridine, quinolinyl, quinoxalinyl,thiazolyl, or thiophenyl.

In some embodiments, both aryls are phenyl. In some embodiments, bothheteroaryls are selected from a group consisting of at least oneheteroaryl is benzofuranyl, benzo[c]isoxazolyl, benzoxazolyl,benzothiazolyl, dihydrothieno[3,4-b][1,4]dioxinyl, furanyl,imidazo[1,2-a]pyridinyl, indazolyl, indolinyl, indolyl, isoquinolinyl,isoxazolyl, naphthyridinyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolo[3,2-c]pyridinyl, quinolinyl,quinoxalinyl, thiazolyl, or thiophenyl.

In some embodiments, the heteroaryl is pyridinyl, and the pyridinyl ismono-, di-, or tri-substituted as previously defined. In some suchembodiments, the mono-, di-, or tri-substitutions are independentlyheteroaryl, heterocyclyl, heterocyclyl-R³, —N(alkyl)R³, wherein R³ is aspreviously defined.

In some embodiments of the invention, R¹ is aryl or heteroaryl and R² iscycloalkyl, ketocycloalkyl or heterocyclyl. In some embodiments, eitherR¹ or R² is cycloalkyl. In some embodiments, at least one cycloalkyl iscyclobutyl, cyclohexyl, cyclopentyl, or cyclopropyl. In someembodiments, the cycloalkyl is further substituted beyond thetri-substitution previously defined, i.e., the cycloalkyl is substitutedmore than three times as previously described; for example, thecycloalkyl is tetra-substituted with fluorine.

In some embodiments of the invention, at least one cycloalkyl,ketocycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted aspreviously described. In some such embodiments, the 1, 2, or 3substituents are independently selected from the group consisting ofmethyl, methoxy, dimethylamino-ethoxy, amino, methylamino,dimethylamino, cyano, chloro, fluoro, (uranyl and thiophenyl.

In some embodiments, the mono-, di-, or tri-substituents areindependently selected from the group consisting of amino, chloro,cyano, dimethylamino, dimethylamino-ethoxy, methyl, methylamino,methoxy, fluoro, —C(O)NHCH₃, furanyl, pyrrolidinyl, thiophenyl andtrifluoromethyl.

In some embodiments, the compound of the present invention is a compounddisclosed in the Experimental Section below. In some embodiments, thecompound is one from Table 1 or Table 2, below.

Another aspect of the present invention is a composition that comprisesa pharmaceutically effective amount of a compound according to thepresent invention, and a pharmaceutically acceptable carrier orexcipient.

A composition of the present invention may be adapted to any mode ofadministration, such as orally (including sublingually), via implants,parentally (including intravenous, intraperitoneal, intraarticularly andsubcutaneous injections), rectally, intranasally, topically, ocularly(via eye drops), vaginally, and transdermally.

A compound of the present invention can be used either as a free base orin the form of a salt derived from pharmaceutically acceptable acids orbases. The salt includes without limitation the following: salts withinorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, and phosphoric acid, and organic acids e.g., aceticacid, oxalic acid, citric acid, tartaric acid, succinic acid, maleicacid, benzoic acid, benzene sulfonic acid, fumaric acid, malic acid,methane sulfonic acid, pamoic acid, and para-toluene sulfonic acid.Other salts include salts with alkali metals or alkaline earth metals,e.g., sodium, potassium, calcium and magnesium, or with organic bases,including quaternary ammonium salts. Further non-limiting examples ofpharmaceutically acceptable inorganic and organic acid addition saltsinclude those listed in [S. M. Berge et al., J. Sci. 1977, 66, 1: 2, andG. S. Paulekuhn, et al., J. Med. Chem. 2007, 50, 26: 6665-6672].

A compound of the present invention can also be used in the form of anester, carbamate and other conventional prodrug form, which generallywill be a functional derivative of the compound that is readilyconverted to the active moiety in vivo. Also included are metabolites ofa compound of the present invention defined as active species producedupon introduction of the compound into a biological system.

When a compound of the present invention is employed as described above,it may be combined with one or more pharmaceutically acceptableexcipients or carriers, e.g., solvents, diluents and the like. Suchpharmaceutical preparations may be administered orally in such forms astablets, capsules (including, e.g., time release and sustained releaseformulations), pills, lozenges, aerosols, dispersible powders, granules,solutions, suspensions (containing, e.g., a suspending agent, at, e.g.,from about 0.05 to about 5% of suspending agent), syrups (containing,e.g., sugar or a sugar substitute such as aspartame, at, e.g., about 10to about 50% sugar or sugar substitute), elixirs and the like, orparenterally in the form of sterile injectable solutions, suspensions oremulsions containing, e.g., from about 0.05 to about 5% suspending agentin an isotonic medium. Such preparations may contain, e.g., from about25 to about 90% of the active ingredient in combination with thecarrier, more customarily from about 5% and about 60% by weight. Theeffective dosage of an active ingredient (e.g., a compound or salt ofthe present invention and a prodrug or metabolite thereof) employed mayvary depending on the particular compound, salt, prodrug or metaboliteused, the mode of administration, age, weight, sex and medical conditionof the patient, and the severity of the disease, disorder, condition,and/or system being treated. The selection of the appropriateadministration and dosage form for an individual mammal will be apparentto those skilled in the art. Such determinations are routine to aphysician, veterinarian or clinician of ordinary skill in the art (seee.g., Harrison's Principles of Internal Medicine, Anthony Fauci et al.(eds.) 14^(th) ed. New York: McGraw Hill (1998)). Further, the dosageregimen may be adjusted to provide the optimal therapeutic response. Forexample, several divided doses may be administered daily or the dose maybe proportionally reduced as indicated by the needs of the therapeuticsituation.

Solid carriers, e.g., starch, lactose, dicalcium phosphate,microcrystalline cellulose, sucrose and kaolin, liquid carriers, e.g.,sterile water, polyethylene glycols, glycerol, non-ionic surfactants andedible oils such as corn, peanut and sesame oils, may be employed as areappropriate to the nature of the active ingredient and the particularform of administration desired. Adjuvants customarily employed in thepreparation of pharmaceutical compositions may be advantageouslyincluded. Non-limiting examples of adjuvants include flavoring agents,coloring agents, preserving agents, and antioxidants, such as vitamin E,ascorbic acid, BHT and BHA.

An active compound also may be administered parenterally orintraperitoneally. Solutions or suspensions of the active compound as afree base, neutral compound or pharmacologically acceptable salt can beprepared in water suitably mixed with a surfactant such ashydroxypropylcellulose. Dispersions also can be prepared in glycerol,liquid polyethylene glycols and mixtures thereof in oils. Thesepreparations may contain a preservative to prevent the growth ofmicroorganisms under ordinary conditions of storage and use.

The pharmaceutical forms suitable for injectable or infusing use includesterile aqueous solutions, suspensions or dispersions, and sterilepowders for the extemporaneous preparation of sterile injectable orinfusing solutions, suspension or dispersions. In all cases, the formmust be sterile and must be fluid to the extent that easy injectabilityand infusing exists. It must be stable under conditions of manufactureand storage and must be preserved against the contaminating action ofmicroorganisms. The carrier can be a solvent or dispersion mediumcontaining, for example, water, ethanol, and polyol (e.g., glycerol,propylene glycol, and liquid polyethylene glycol), suitable mixturesthereof, and vegetable oil.

Furthermore, active compounds of the present invention can beadministered intranasally or transdermally using vehicles suitable forintranasal or transdermal delivery known to those ordinarily skilled inthe art. Transdermal administration includes all administrations acrossthe surface of the body and the inner linings of bodily passagesincluding epithelial and mucosal tissues, using carrier systems such aslotions, creams, foams, pastes, patches, suspensions, solutions, andsuppositories (rectal and vaginal). Creams and ointments may be viscousliquid or semisolid emulsions of either the oil-in-water or water-in-oiltype. Pastes comprised of absorptive powders dispersed in petroleum orhydrophilic petroleum containing the active ingredient also may besuitable. A variety of occlusive devices may be used to release theactive ingredient into the blood stream such as a semi-permeablemembrane covering a reservoir containing the active ingredient with orwithout a carrier, or a matrix containing the active ingredient. Otherocclusive devices are known in the literature. When using a transdermaldelivery system, the dosage administration will be continuous ratherthan a single or divided daily dose.

A compound of the present invention can also be administered in the formof a liposome delivery system where the liposomal lipid bilayer isformed from a variety of phospholipids. A compound of the presentinvention also may be delivered by the use of a carrier such asmonoclonal antibodies to which the compound is coupled. Other carriersto which a compound of the present invention also may be coupled are asoluble polymer or a biodegradable polymer useful in achievingcontrolled release of an active ingredient.

It is understood by those practicing the art that some of the compoundsof the present invention may contain one or more asymmetric centers, andthus may give rise to enantiomers and diastereomers. The presentinvention includes all stereoisomers including individual diastereomersand resolved, enantiomerically pure stereoisomers, as well as racemates,and all other variations of stereoisomers, and mixtures andpharmaceutically acceptable salts thereof, which possess the indicatedactivity. Optical isomers may be obtained in pure form by customaryprocedures known to those skilled in the art, and include, but are notlimited to, chiral chromatographic separations, diastereomeric saltformation, kinetic resolution, and asymmetric synthesis. It is alsounderstood that this invention encompasses all possible regioisomers,endo-exo isomers, and mixtures thereof that possess the indicatedactivity. Such isomers can be obtained in pure form by customaryprocedures known to those skilled in the art, and include, but are notlimited to, column chromatography, thin-layer chromatography, andhigh-performance liquid chromatography. It is understood by thosepracticing the art that some of the compounds of the present inventionmay be chiral due to hindered rotation, and give rise to atropisomers,which can be resolved and obtained in pure form by customary proceduresknown to those skilled in the art. It is further understood by thosepracticing the art that some of the compounds of the present inventioninclude structural isomers, including tautomers.

Included also in this invention are all polymorphs and hydrates of thecompounds of the present invention.

Another aspect of the present invention is a use or a method for usingthe compounds of the invention. The invention is to be understood asembracing all simultaneous, sequential or separate use of anycombination of the compounds of the invention with any pharmaceuticalcomposition useful in the methods described herein.

In some embodiments, the use or method includes administering aneffective amount of a combination of two or more of the compoundsdescribed herein, or salts thereof. It is specifically intended that thephrases “combination of two or more of the compounds described herein,or salts thereof,” or “at least one compound as described herein, or apharmaceutically acceptable salt thereof,” or similar languagedescribing specific compounds, includes the administration of suchcompounds in any proportion and combination of salt, neutral or freebase forms; i.e., includes the administration of such compounds each inthe base form, each in the neutral form or each in the salt form, or oneor more in the base form and one or more in the neutral form, or one ormore in the base form and one or more in the salt form, or one or morein the neutral form and one or more in the salt form, in any proportionof the neutral and/or basic compounds and/or salts.

As used herein, the phrase “effective amount” when applied to a compoundof the invention, is intended to denote an amount sufficient to cause anintended biological effect. The phrase “therapeutically effectiveamount” when applied to a compound of the invention is intended todenote an amount of the compound that is sufficient to ameliorate,palliate, stabilize, reverse, slow or delay the progression of adisorder or disease state, or of a symptom of the disorder or disease.In some embodiments, the method of the present invention provides foradministration of combinations of compounds. In such instances, the“effective amount” is the amount of the combination sufficient to causethe intended biological effect.

The term “treatment” or “treating” as used herein means curing,ameliorating or reversing the progress of a disease or disorder, orameliorating or reversing one or more symptoms or side effects of suchdisease or disorder. “Treatment” or “treating”, as used herein, alsomeans to inhibit or block, as in retard, arrest, restrain, impede orobstruct, the progress of a system, condition or state of a disease ordisorder. For purposes of this invention, “treatment” or “treating”further means an approach for obtaining beneficial or desired clinicalresults, where “beneficial or desired clinical results” include, withoutlimitation, alleviation of a symptom, diminishment of the extent of adisorder or disease, stabilized (i.e., not worsening) disease ordisorder state, delay or slowing of a disease or disorder state,amelioration or palliation of a disease or disorder state, and remissionof a disease or disorder, whether partial or total, detectable orundetectable.

The term “prevent” or “preventing” as used herein means to keep fromhappening or existing. The term “administering” as used herein refers toeither directly administering a compound of the present invention, oradministering a prodrug, derivative, or analog of same, that will forman effective amount of the compound within a mammal.

The present invention also provides a method of treating a disease ordisorder, the method comprises administering a therapeutically effectiveamount of at least one compound of the present invention or apharmaceutically acceptable salt thereof to a mammal in need thereof,wherein the disease or disorder is a central nervous system disease ordisorder.

The present invention also provides a use of a compound of formula (I),including a pharmaceutically acceptable salt thereof, in the preparationof a medicament for the treatment of a central nervous system disease ordisorder. The present invention further provides a compound of formula(I) for use in treating a disease or disorder.

A compound of formula (I) can allosterically modulate the mGlu5receptor. An allosteric modulator that enhances or potentiates theaffinity of an orthosteric ligand for the mGluR5 receptor and/orenhances or potentiates an orthosteric agonist's efficacy is anallosteric enhancer (or potentiator) or positive allosteric modulator(PAM). See e.g., May, L. T. Annu. Rev. Pharmacol. Toxicol. 2007, 47,1-51. An allosteric modulator that reduces or diminishes the affinity ofan orthosteric ligand for the mGluR5 receptor and/or reduces ordiminishes an orthosteric agonist's efficacy is an allosteric antagonist(or inhibitor) or negative allosteric modulator (NAM). Id.

In some embodiments, the mammal of the method of the invention is ahuman.

In some embodiments of the method or use of the invention, the centralnervous system disease or disorder is a cognitive or neurodegenerativedisease or disorder. In some such embodiments, the cognitive orneurodegenerative disease or disorder is selected from a groupconsisting of a mood disorder, an anxiety, a schizophrenia (includingschizoaffective disorders), Alzheimer's disease, Parkinson's disease,multiple sclerosis, Huntington's chorea, amyotrophic lateral sclerosis,Creutzfeld-Jakob disease, a trauma-induced neurodegeneration,AIDS-induced encephalopathy, another infection-related encephalopathy(i.e., a non-AIDS-induced encephalopathy), Fragile X syndrome, an autismspectrum disorder, and a combination thereof.

As used herein, the phrase “mood disorder” refers to any of severalpsychological disorders characterized by abnormalities of emotionalstate, such as, without limitation, bipolar disorders, depressivedisorders, cyclothymic disorders, dysthymic disorders, mood disordersdue to a general medical condition, mood disorders not otherwisespecified and substance-induced mood disorders; and as characterized bythe Diagnostic and Statistical Manual of Mental Disorders, FourthEdition (DSM-IV) (American Psychiatric Association: Arlington, Va.,1994).

As used herein, the phrase “autism spectrum disorder” (ASD) refers to adisorder that causes severe and pervasive impairment in thinking,feeling, language, and the ability to relate to others, which is oftenfirst diagnosed in early childhood and range from a severe form, calledautistic disorder (“classic” autism), through pervasive developmentdisorder not otherwise specified (PDD-NOS), to a much milder form,Asperger syndrome. The phrase, as used herein, also includes Rettsyndrome and childhood disintegrative disorder, and as used herein, issynonymous with the phrase, “pervasive developmental disorders” (PDDs).

In some such embodiments, the mood disorder is a depression (i.e., adepressive disorder). In some such embodiments, the depression isselected from the group consisting of atypical depression, bipolardepression, unipolar depression, major depression, endogenous depression(i.e., acute depression with no obvious cause), involutional depression(i.e., depression that occurs in mid-life or the elderly), reactivedepression (i.e., depression caused by an obvious traumatic lifeepisode), postpartum depression, primary depression (i.e., depressionthat has no obvious physical or psychological cause such as a medicalillness or disorder), psychotic depression, and secondary depression(i.e., depression that seems to be caused by some other underlyingcondition such another medical illness or disorder).

In some such embodiments, the anxiety disease or disorder is selectedfrom a group comprising generalized anxiety disorder, panic anxiety,obsessive compulsive disorder, social phobia, performance anxiety,post-traumatic stress disorder, acute stress reaction, an adjustmentdisorder, a hypochondriacal disorder, separation anxiety disorder,agoraphobia, a specific phobia, anxiety disorder due to general medicalcondition, substance-induced anxiety disorder, alcoholwithdrawal-induced anxiety, and a combination thereof.

In some embodiments, the central nervous system disease or disorder ofthe method or use comprising a compound of the invention is a seizuredisease or disorder. In some embodiments, the seizure disease ordisorder is selected from the group consisting of a convulsion,epilepsy, status epilepticus, and a combination thereof.

In some embodiments, the central nervous system disease or disorder ofthe method or use comprising a compound of the invention is a paindisease or disorder selected from the group consisting of inflammatorypain, neuropathic pain and migraine pain. In some embodiments, theneuropathic pain or migraine pain disease or disorder is selected fromthe group consisting of allodynia, hyperalgesic pain, phantom pain,neuropathic pain related to diabetic neuropathy, neuropathic painrelated to migraine, and a combination thereof.

In some embodiments, the central nervous system disease or disorder ofthe method or use comprising a compound of the invention is a neuronalhyperexcitation state disease or disorder. In some embodiments, theneuronal hyperexcitation state disease or disorder is a neuronalhyperexcitation state in medicament withdrawal, a neuronalhyperexcitation state in intoxication, or a combination thereof.

In some embodiments of the method or use comprising a compound of theinvention, at least one symptom of the cognitive neurodegenerative,psychiatric or neurological disease or disorder is treated.

In some embodiments, the cognitive, neurodegenerative, psychiatric orneurological disease or disorder is a depression. In some suchembodiments, the at least one symptom of the depression is depressedfeeling, depressed mood, loss of interest or pleasure in some or allactivities, changes in appetite, changes in weight, changes in sleeppatterns, lack of energy, fatigue, low self esteem, diminished capacityfor thinking, concentration, or decisiveness, feelings of hopelessnessor worthlessness, psychomotor agitation or retardation, self-reproach,inappropriate guilt, frequent thoughts of death or suicide, plans orattempts to commit suicide, or a combination thereof.

In some embodiments, the cognitive, neurodegenerative, psychiatric orneurological disease or disorder is an anxiety. In some suchembodiments, the at least one symptom of anxiety is apprehension, fear,trembling, muscle aches, insomnia, abdominal upsets, dizziness,irritability, persistent, recurring thoughts, compulsions, heartpalpitations, chest pain, chest discomfort, sweating, tinglingsensations, feeling of choking, fear of losing control, flashbacks,nightmares, intrusive thoughts, intrusive recollections, avoidancebehaviors, emotional numbing, an inability to sleep, anxious feelings,overactive startle response, hypervigilance, outbursts of anger,faintness, blushing, profuse sweating, or a combination thereof.

In some embodiments, the cognitive, neurodegenerative, psychiatric orneurological disease or disorder is schizophrenia. In some suchembodiments, the at least one symptom of schizophrenia is a positivesymptom selected from the group consisting of hallucination, delusion,paranoia, and a combination thereof. In some such embodiments, thesymptom of schizophrenia is a negative symptom selected from the groupconsisting of social withdrawal, flat affect, anhedonia, decreasedmotivation, and a combination thereof. In some such embodiments, thesymptom of schizophrenia is a cognitive symptom selected from the groupconsisting of severe deficit in attention, severe deficit in objectnaming, severe deficit in working memory, severe deficit in long-termmemory storage, severe deficit in executive functioning, a slowing ofinformation processing, a slowing of neural activity, long termdepression, and a combination thereof.

In some embodiments of the method or use comprising a compound of theinvention, the cognitive, neurodegenerative, psychiatric or neurologicaldisease or disorder is Parkinson's disease. In some such embodiments,the at least one symptom of Parkinson's disease is levodopa-induceddyskinesia, poor balance, Parkinsonian gait, bradykinesia, rigidity,tremor, change in speech, loss of facial expression, micrographia,difficulty swallowing, drooling, pain, dementia, confusion, a sleepdisturbance, constipation, a skin problem, depression, fear, anxiety,difficulty with memory, slowed thinking, sexual dysfunction, an urinaryproblem, fatigue, aching, loss of energy, or a combination thereof.

in some embodiments, the cognitive, neurodegenerative, psychiatric orneurological disease or disorder is Alzheimer's disease. In some suchembodiments, the at least one symptom of Alzheimer's disease isimpairment in memory, impairment in attention, impairment in judgment,impairment in decision-making, impairment in orientation to physicalsurroundings, language impairment, impairment in speed-dependentactivities, impairment in abstract reasoning, impairment in visuospatialabilities, impairment in executive functioning, impairment in behavioraldisturbances, disinterest and passivity, apathy, inappropriate dressing,poor self care, agitation, violent outburst, aggression, depression,anxiety, hallucination, delusion, change in personality, change in mood,dementia, or a combination thereof.

In some embodiments, the cognitive, neurodegenerative, psychiatric orneurological disease or disorder is multiple sclerosis. In some suchembodiments, the at least one symptom of multiple sclerosis is opticneuritis blurred vision, eye pain, loss of color vision, blindness,diplopia double vision, nystagmus jerky eye movements, ocular dysmetria,constant under- or overshooting eye movements, internuclearophthalmoplegia, nystagmus, diplopia, movement and sound phosphenes,diplopia, afferent pupillary defect, motor paresis, monoparesis,paraparesis, hemiparesis, quadraparesis plegia, paraplegia, hemiplegia,tetraplegia, quadriplegia, spasticity, dysarthria, muscle atrophy,spasms, cramps, hypotonia, dorms, myoclonus, myokymia, restless legsyndrome, footdrop dysfunctional reflexes (MRSs, Babinski's, Hoffman's,Chaddock's), paraesthesia, anaesthesia, neuralgia, neuropathic pain,neurogenic pain, l'hermitte's, proprioceptive dysfunction, trigeminalneuralgia, ataxia, intention tremor, dysmetria, vestibular ataxia,vertigo, speech ataxia, dystonia, dysdiadochokinesia, frequentmicturation, bladder spasticity, flaccid bladder, detrusor-sphincterdyssynergia, erectile dysfunction, anorgasmy, retrograde ejaculation,frigidity, constipation, fecal urgency, depression, cognitivedysfunction, dementia, mood swings, emotional lability, euphoria,bipolar syndrome, anxiety, aphasia, dysphasia, fatigue, uhthoffssymptom, gastroesophageal reflux, a sleeping disorder, or a combinationthereof.

The present invention further provides a method of treatinggastroesophageal reflux, the method comprises administering atherapeutically effective amount of at least one compound of claim 1 ora pharmaceutically acceptable salt thereof to a mammal in need thereof.The present invention further provides a use of a compound of theinvention in the preparation of a medicament for the treatment ofgastroesophageal reflux. The present invention further provides acompound of the invention for use in treating gastroesophageal reflux.

The present invention further provides a method of treating alcoholdependence, the method comprises administering a therapeuticallyeffective amount of at least one compound of claim 1 or apharmaceutically acceptable salt thereof to a mammal in need thereof.The present invention further provides a use of a compound of theinvention in the preparation of a medicament for the treatment ofalcohol dependence. The present invention further provides a compound ofthe invention for use in treating alcohol dependence.

In some embodiments, the compound of the present invention is used inthe preparation of a medicament for treatment of a central nervoussystem disease or disorder. In some embodiments, the central nervousdisease or disorder is as previously disclosed herein.

Another aspect of the present invention is a process for producing thecompounds of the present invention.

Preparation of the Compounds of the Present Invention

The compounds of the present invention may be prepared, withoutlimitation, according to one of the general methods outlined below. Forexample, Schemes 1-9 that follow are intended as an illustration of someembodiments of the invention and no limitation of the present inventionis implied because of them.

The following defines acronyms as used herein unless specified otherwisein a particular instance.

BINAP=2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, CAS No. 98327-87-8;BOP=benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate, CAS No. 56602-33-6; DCM=dichloromethane ormethylene chloride; DIEA=DIPEA=N,N-diisopropylethylamine, CAS No.7087-68-5; DMA=N,N-dimethylacetamide, CAS No. 127-19-5;DMC=dimethylimidazolinium chloride; DMF=N,N-dimethylformamide, CAS No.68-12-2; DPPA=Diphenylphosphoryl azide, CAS No. 26386-88-9;EDCI=N-Ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride, CASNo. 93128-40-6;HATU=2-(7-Azabenzotriazole-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate, CAS No. 873798-09-5;HBTU=2-(1H-Benzotriazole-1-yl)-1,1,3,3-Tetramethyluroniumhexafluorophosphate, CAS No. 94790-37-1; NMP=N-Methyl-Pyrrolidone, CASNo. 872-50-4; PyBOP=benzotriazol-1-yl-oxytripyrrolidinophosphoniumhexafluorophosphate, CAS No. 128625-52-5; RT or rt=room temperature;TEA=triethanolamine, CAS No. 102-71-6; THF=tetrahydrofuran, CAS No.109-99-9; and TMSOK=potassium trimethylsilanolate, CAS No. 10519-96-7

Symmetrical amides of the formula (I-A) (R¹═R²) can be prepared via theprocess outlined in Scheme 1 using customary amidation procedures fromintermediate A, where R¹ is equal to R², and R¹ and R² are as previouslydefined herein.

Unsymmetrical amides of formula (I-A) (R¹≠R²) can be prepared via theprocess outlined in Scheme 2. Amidation of intermediate A with a mixtureof R¹COCl and R²COCl, or a mixture of R¹CO₂H and R²CO₂H using customaryamidation procedures affords unsymmetrical amides of formula (I-A),where R¹ and R² are as previously defined herein.

Compounds of formula (I-A) can also be made via the process outlined inScheme 3. Amidation of intermediate B with R²COCl or R²CO₂H usingcustomary amidation procedures affords unsymmetrical amides of formula(I-A).

Compounds of formula (I-B) can be made via the process outlined inScheme 4 or 5 using customary amidation procedures from intermediate Cor D, respectively

Intermediate A can be made via the process outlined in Scheme 6.Esterification of commercially available cyclohexane-1,3-dicarboxylicacid 1 under conditions such as in methanol in the presence ofchlorotrimethylsilane affords ester 2. Alkylation of compound 2 with1-bromo-2-chloroethane in the presence of base produces bicycliccompound 3. Saponification of 3 under standard conditions givescarboxylic acid 4, which is converted to diamine intermediate A via astandard Curtius rearrangement, followed by the treatment with aqueous(aq.) HCl.

Intermediate B can be made via the process outlined in Scheme 7.Mono-hydrolysis of di-ester 2 by treatment with base such as 0.5 eqBa(OH)₂ in methanol affords carboxylic acid 5, which was converted tobenzyl carbamate 6 via standard Curtius rearrangement, followed by thetreatment with benzyl alcohol. Saponification of compound 6 understandard conditions produces carboxylic acid 7, which was converted tocompound 8 via standard Curtius rearrangement, followed by the treatmentwith tert-butyl alcohol. Removal of benzyl group under standardconditions such as hydrogenation gives amine 9. Customary amidation ofamine 9 with R¹CO₂H followed by removal of BOC (butoxycarbonyl)protecting group under standard conditions affords intermediate B.

Intermediate B and C can be made via the process outlined in Scheme 8.Removal of benzyl protecting group of compound 6 under standardconditions such as hydrogenation gives amine 10. Customary amidation of1.0 with R¹CO₂H or R¹COCl yields amide 11. Saponification of compound 11under standard conditions produces intermediate C, which upon Curtiusrearrangement followed by the treatment with aq. HCl, affordsintermediate B.

Intermediate D can be made via the process outlined in Scheme 9.Amidation of compound 5 and R²NH₂ using customary conditions affordscompound 12. Saponification of ester 12 under standard conditions yieldscarboxylic acid 13, which upon standard Curtius rearrangement followedby the treatment of aq. HCl, yields intermediate D.

Experimental Section

1. General Methods

Unless specifically stated otherwise, the experimental procedures wereperformed under the following conditions. All operations were carriedout at room temperature (about 18° C. to about 25° C.) under nitrogenatmosphere. Evaporation of solvent was carried out using a rotaryevaporator under reduced pressure or in a high performance solventevaporation system HT-4X. (Genevac Inc., Gardiner, N.Y., USA). Thecourse of the reaction was followed by thin layer chromatography (TLC)or liquid chromatography-mass spectrometry (LC-MS), and reaction timesare given for illustration only. Silica gel chromatography was carriedout on a CombiFlash® system (Teledyne Isco, Inc., Lincoln, Nebr., USA)with pre-packed silica gel cartridge or performed on Merck silica gel 60(230-400 mesh). The structure and purity of all final products wasassured by at least one of the following analytical methods: nuclearmagnetic resonance (NMR) and LC-MS. NMR spectra was recorded on a BrukerAvance™ 300 spectrometer (Bruker BioSpin Corp., Billerica, Mass., USA)or a Varian UNITY INOVA™ 400 (Varian, Inc., Palo Alto, Calif., USA) orBruker AVANCE III 500 MHz UltraShield-Plus™ Digital NMR Spectrometerusing the indicated solvent. Chemical shift (δ) is given in parts permillion (ppm) relative to tetramethylsilane (TMS) as an internalstandard. Coupling constants (J) are expressed in hertz (Hz), andconventional abbreviations used for signal shape are: s=singlet;d=doublet; t=triplet; m=multiplet; br=broad; etc. Unless statedotherwise, mass spectra were obtained using electrospray ionization(ESMS) via a Micromass® Platform II system or a Quattro Micro™ system(both from Waters Corp., Milford, Mass., USA) or 1200RRLC/6140 SQ system(Agilent Technologies, Santa Clara, Calif., USA), and (M+H)⁺ isreported.

PREPARATION OF INTERMEDIATES OF THE INVENTION

Unless specified otherwise, all starting materials and reagents wereobtained from commercial suppliers, such as Sigma-Aldrich (St. Louis,Mo., USA) and its subsidiaries, and used without further purification.

Intermediate 1 Bicyclo[2.1]octane-1,5-diamine dihydrochloride

Intermediate 1 was prepared via the process of Scheme 6, supra, asfollows:

Step 1: Cyclohexane-1,3-dicarboxylic acid dimethyl ester

1,3-Cyclohexanedicarboxylic acid (45.0 g, 261.4 mmol) was dissolved inmethanol (250 mL). Chlorotrimethylsilane (10.00 mL, 78.79 mmol) wasadded and the reaction was stirred at room temperature for 4 days. Thereaction was checked by LC-MS with the product mass [M+H]⁺201 seen. Themixture was concentrated under reduced pressure. The resulting residuewas diluted with dichloromethane (200 mL). The organic layer was thenwashed with saturated. NaHCO₃, dried over sodium sulfate, filtered andconcentrated under reduced pressure to give a slightly viscous, clearand colorless oil. The oil was redissolved in anhydrous THF andconcentrated to yield 49.5 g (95%) of cyclohexane-1,3-dicarboxylic aciddimethyl ester, which was used in the next step without furtherpurification.

Step 2: Bicyclo[3.2.1]octane-1,5-dicarboxylic acid dimethyl ester

A solution of N,N-diisopropylamine (4.5 mL, 32 mmol) in tetrahydrofuran(25 mL) was cooled at −78° C. and treated with 1.6 M of n-butyllithiumin hexane (19 mL). The reaction was warmed to 0° C., stirred for 5minutes, then cooled back to −78° C.1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (15 mL, 120 mmol) wasadded dropwise over 20 minutes, then a solution ofcyclohexane-1,3-dicarboxylic acid dimethyl ester (5.0 g, 25 mmol) intetrahydrofuran (10 mL) was added dropwise and the mixture stirred for 1hour at the same temperature. Then a solution of 1-bromo-2-chloroethane(2.9 mL, 35 mmol) in tetrahydrofuran (8 mL) was added dropwise. Thereaction was allowed to return slowly to room temperature and stirredovernight. The reaction mixture was cooled to 0° C. and quenched withsaturated ammonium chloride solution. The reaction mixture wasconcentrated under reduced pressure and the resulting residue wasdiluted with a small amount of water and extracted with dichloromethane(4×50 mL). The organic layers were combined, dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure. Theresulting residue was purified with chromatography to give theintermediate 1-(2-chloro-ethyl)-cyclohexane-1,3-dicarboxylic aciddimethyl ester (1.22 g). A solution of N,N-diisopropylamine (0.91 mL,6.50 mmol) in tetrahydrofuran (10 mL) was cooled at −78° C. and treatedwith 1.6 M of n-butyllithium in hexane (4.06 mL). The reaction waswarmed to 0° C., stirred for 5 minutes, and then cooled back to −78° C.1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.24 mL, 18.6 mmol)was added dropwise over 20 minutes, then a solution of1-(2-chloro-ethyl)-cyclohexane-1,3-dicarboxylic acid dimethyl ester(1.22 g, 4.64 mmol) in tetrahydrofuran (10 mL) was added dropwise andthe mixture was stirred for 1 hour at the same temperature. The reactionwas allowed to return slowly at room temperature and stirred overnight.The reaction was quenched with saturated ammonium chloride solution andconcentrated under reduced pressure. The resulting residue was dilutedwith a small amount of water and extracted with dichloromethane (4×50mL). The organic layers were combined, dried over anhydrous sodiumsulfate, filtered, and evaporated to give crude product (3.05 g)containing DMPU. The product was used in the next step without furtherpurification.

Step 3: Bicyclo[3.2.1]octane-1,5-dicarboxylic acid

A solution of bicyclo[3.2.1]octane-1,5-dicarboxylic acid dimethyl ester(crude 3.01 g from step 2) in tetrahydrofuran (100 mL) was treated with1 M of lithium hydroxide in water (75 mL) and warmed at 70° C. for 6hours. The reaction was concentrated under reduced pressure and theresulting residue was partitioned between water and ethyl acetate. Theaqueous layer was collected and washed again with ethyl acetate. Theaqueous layer was acidified with 1N HCl to pH 2, and then extracted withethyl acetate. The organic layer was collected, dried over anhydroussodium sulfate, filtered, and evaporated to afford 725 mg of whitesolid, which was used in the next step without further purification.

Step 4: Bicyclo[3.2.1]octane-1,5-diamine dihydrochloride

A mixture of bicyclo[3.2.1]octane-1,5-dicarboxylic acid (725 mg, 3.66mmol) in toluene (60 mL) was treated with triethylamine (1.53 mL, 11.0mmol) followed by diphenylphosphonic azide (1.97 mL, 9.14 mmol). Thereaction was heated at 90° C. for 3 hours, then cooled down to rt andconcentrated under reduced pressure. The resulting residue was cooled inan ice bath and treated with 6 M of hydrogen chloride in water (60 mL).The ice bath was removed and the reaction was stirred overnight. Most ofthe water was removed in vacuo and the resulting residue was stirredwith acetonitrile in an ice bath until a colorless precipitatedeposited. The precipitate was collected by filtration and dried undervacuum to give product as a colorless solid (250 mg, 32%), which wasused in the next step without further purification.

Intermediate 2 6-Methyl-pyrazine-2-carboxylic acid(5-amino-bicyclo[3.2.1]oct-1-yl)-amide HCl salt

Intermediate 2 was prepared via the processes of Schemes 7 and 8, supra,as follows:

Step 1: Bicyclo[3.2.1]octane-1,5-dicarboxylic acid diethyl ester

Using the similar experimental procedure described in the synthesis ofintermediate 1 (step 2), bicyclo[3.2.1]octane-1,5-dicarboxylic aciddiethyl ester was prepared from cyclohexane-1,3-dicarboxylic aciddiethyl ester at 0.18 mol reaction scale. ESI-MS m/z: 277 (M+H)⁺

Step 2: Bicyclo[3.2.1]octane-1,5-dicarboxylic acid monoethyl ester

Partial hydrolysis of the cyclized diethyl ester 4 (1.3 g) was done byusing barium hydroxide (0.5 equiv) in ethanol (13 mL) and water (3 mL)at ambient temperature for 18 hours. The reaction was concentrated underreduced pressure and the resulting residue was partitioned between waterand ethyl acetate. The aqueous layer was collected and washed again withethyl acetate. The aqueous layer was acidified with 1N HCl to pH 2, andthen extracted with ethyl acetate. The organic layer was collected,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by column chromatography toafford 500 mg (47%) of the desired product. ESI-MS m/z: 227 (M+H)⁺

Step 3: 5-Benzyloxycarbonylamino-bicyclo[3.2.1]octane-1-carboxylic acidethyl ester

Using the similar experimental procedure described in the synthesis ofintermediate 1 (step 4),5-benzyloxycarbonylamino-bicyclo[3.2.1]octane-1-carboxylic acid ethylester was made from bicyclo[3.2.1]octane-1,5-dicarboxylic acid monoethylester via Curtius rearrangement with DPPA and TEA in toluene, andquenched with BnOH at 1.1-10.3 mmol reaction scales. ESI-MS m/z: 332(M+H)⁺

Step 4: 5-Amino-bicyclo[3.2.1]octane-1-carboxylic acid ethyl ester

5-Benzyloxycarbonylamino-bicyclo[3.2.1]octane-1-carboxylic acid ethylester (2.0 g, 6.05 mmol) was dissolved in ethanol (50.0 mL). Pd/C (10%)(0.32 g, 0.30 mmol) was added. The mixture was hydrogenated under 50 psiH₂ at rt for 6 hrs. The catalyst was removed by filtration through alayer of Celite. The filtrate was concentrated under reduced pressure toafford 1.0 g (84%) of the desired product. ESI-MS m/z: 198 (M+H)⁺

Step 5:5-[(6-Methyl-pyrazine-2-carbonyl)-amino]-bicyclo[3.2.1]octane-1-carboxylicacid ethyl ester

5-Amino-bicyclo[3.2.1]octane-1-carboxylic acid ethyl ester (0.5 g, 2.53mmol) was dissolved in methylene chloride (10.0 mL, 156 mmol).6-Methylpyrazine-2-carboxylic acid (0.35 g, 2.53 mmol),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(1.12 g, 2.53 mmol) and triethylamine (0.71 mL, 5.07 mmol) in methylenechloride (10.0 mL, 156 mmol) were added. The mixture was stirred at rtfor 2 hours. The mixture was concentrated under reduced pressure. Theresulting residue was purified on the CombiFlash® system (hexane/ethylacetate: 100/0 to 30/70 in 8 min, then hexane/ethyl acetate: 30/70) toafford 0.60 g (75%) of the desired product. ESI-MS m/z: 318 (M+H)⁺

Step 6:5-[(6-Methyl-pyrazine-2-carbonyl)-amino]-bicyclo[3.2.1]octane-1-carboxylicacid

5-[6-Methyl-pyrazine-2-carbonyl)-amino]-bicyclo[3.2.1]octane-1-carboxylicacid ethyl ester (0.60 g, 1.89 mmol) was dissolved in tetrahydrofuran(10.0 mL, 123 mmol). Lithium hydroxide monohydrate (0.40 g, 9.45 mmol)in water (6.0 mL, 333 mmol) was added. The mixture was stirred at rtovernight. The mixture was concentrated under reduced pressure. Theresulting residue was participated in ethyl acetate (20 mL) and water(20 mL). The aqueous layer was collected, acidified with 1N HCl to pH 2,and extracted with ethyl acetate (60 mL). The organic layer was washedwith brine, dried over Na₂SO₄ and concentrated to afford 340 mg (62%) ofthe desired product as white solid. It was used in the next step withoutfurther purification. ESI-MS m/z: 290 (M+H)⁺

Step 7: 6-Methyl-pyrazine-2-carboxylic acid(5-amino-bicyclo[3.2.1]oct-1-yl)-amide HCl salt

5-[(6-Methyl-pyrazine-2-carbonyl)-amino]-bicyclo[3.2.1]octane-1-carboxylicacid (0.340 g, 1.18 mmol) was suspended in toluene (10.0 mL, 93.9 mmol).Triethylamine (0.20 mL, 1.41 mmol) was added, followed by the additionof diphenylphosphonic azide (0.25 mL, 1.18 mmol). The mixture wasstirred at rt for 2 hours. Then the mixture was heated at 90° C. for 1hour. The mixture was cooled down and poured into ice-cold 6M aqueousHCl and stirred overnight. The aqueous layer was collected, cooled downat 0° C., basified with solid K₂CO₃ to pH 11, and extracted with CH₂Cl₂(4×25 mL). The combined organic layer was dried over Na₂SO₄ andconcentrated under reduced pressure. The resulting residue was dissolvedin CH₂Cl₂, 4 M HCl/dioxane (1.0 mL). The mixture was concentrated underreduced pressure to afford 345 mg (99%) of6-methyl-pyrazine-2-carboxylic acid(5-amino-bicyclo[3.2.1]oct-1-yl)-amide HCl salt as a white solid. It wasused in the next step without further purification. ESI-MS m/z: 261(M+H)⁺.

Intermediate 3 N-(5-Aminobicyclo[3.2.1]octan-1-yl)-3-fluorobenzamide

Step 1: Dimethyl cyclohexane-1,3-dicarboxylate

To a solution of 1,3-cyclohexanedicarboxylic acid (25 g, 0.145 mol) inmethanol (250 mL) was added concentrated H₂SO₄ (10 mL) and the reactionsolution was refluxed overnight. After cooled to room temperature,methanol was removed under reduced pressure. The residue was dilutedwith ethyl acetate (500 mL), washed with Sat. Na₂CO₃ (2×300 mL) andbrine (100 mL), dried over MgSO₄ and concentrated under reduced pressureto give 27.4 g (94%) of dimethyl cyclohexane-1,3-dicarboxylate as alight yellow oil. ESI-MS m/z: 201 (M+H)⁺.

Step 2: Dimethyl 1-(3-chloropropyl)cyclohexane-1,3-dicarboxylate

To a pre-cooled (−78° C.) solution of lithium diisopropylamide (36 mL,78 mmol) in THF (250 mL) was added DMPU (30.5 g, 238 mmol) dropwise (notallowing the temperature to exceed −65° C.), followed by an addition ofa solution of dimethyl cyclohexane-1,3-dicarboxylate (11.9 g, 59.5 mmol)in THF (50 mL) at −78° C. over 20 min. After stirring at −78° C. for onehour, 1-bromo-2-chloroethane (11.1 g, 77.4 mmol) was added and thereaction mixture was slowly warmed up to room temperature overnight.After quenched with Sat. NH₄Cl (100 mL), the mixture was concentratedunder reduced pressure. The resulting residue was diluted with water(200 mL) and extracted with dichloromethane (4×100 mL). The combinedorganic layer was washed with water (100 mL) and brine (100 mL), driedover MgSO₄ and concentrated under reduced pressure. The resultingresidue was purified by column chromatography (silica gel, petroleumether/ethyl acetate: 20/1) to afford 11.7 g (75%) of dimethyl1-(3-chloropropyl)cyclohexane-1,3-dicarboxylate as a yellow oil. ESI-MSm/z: 263 (M+H)⁺.

Step 3: Dimethyl bicyclo[3.3.1]nonane-1,5-dicarboxylate

To a pre-cooled (−78° C.) solution of lithium diisopropylamide (27 mL,54 mmol) in THF (80 mL) was added DMPU (30.2 g, 236 mol) dropwise,followed by an addition of dimethyl1-(3-chloropropyl)cyclohexane-1,3-dicarboxylate (11.7 g, 44.7 mmol) inTHF (50 mL) within 20 min. The reaction mixture was stirred for 30 minat −78° C. and then allowed to warm up to room temperature over a periodof 1.5 h. After quenched with saturated ammonium chloride (100 mL), themixture was concentrated under reduced pressure. The residue was dilutedwith water (300 mL) and extracted with dichloromethane (4×100 mL). Thecombined organic layer was washed with water (100 mL) and brine (100mL), dried over MgSO₄ and concentrated under reduced pressure. Theresidue was purified by column chromatography (silica gel, petroleumether/ethyl acetate: 20/1) to afford 8.32 g (82%) of dimethylbicyclo[3.3.1]nonane-1,5-dicarboxylate as a light yellow oil. ESI-MSm/z: 227 (M+H)⁺.

Step 4: 5-(methoxycarbonyl)bicyclo[3.3.1]nonane-1-carboxylic acid

A solution of dimethyl bicyclo[3.3.1]nonane-1,5-dicarboxylate (8.32 g,36.8 mmol) and Ba(OH)₂.8H₂O (5.80 g, 18.4 mmol) in ethanol (40 mL) andH₂O (10 mL) was refluxed overnight. After cooled to room temperature,the mixture was concentrated under reduced pressure. The resultingresidue was added diluted with water (100 mL) and extracted with diethylether (3×200 mL). The combined organic layer was washed with brine (100mL), dried over sodium sulfate and concentrated under reducer pressureto recover starting material as an orange oil. The aqueous phase wasadjusted to pH 1˜2 with 2N aq. HCl, and extracted with dichloromethane(3×100 mL). The combined organic layer was washed with brine (100 mL),dried over sodium sulfate and concentrated under reduced pressure toafford 1.8 g (67%) of5-(methoxycarbonyl)bicyclo[3.3.1]nonane-1-carboxylic acid as a whitesolid. ESI-MS m/z: 213 (M+H)⁺.

Step 5: Methyl5-(benzyloxycarbonylamino)bicyclo[3.2.1]octane-1-carboxylate

A mixture of 5-(methoxycarbonyl)bicyclo[3.3.1]nonane-1-carboxylic acid(5.23 g, 24.7 mmol), diphenylphosphonic azide (8.0 mL, 36.9 mmol) andtriethylamine (1.0 mL, 136 mmol) in toluene (150 mL) was stirred at roomtemperature for one hour, and then refluxed for three hours. Benzylalcohol (4.0 mL, 38.7 mmol) was added, and the mixture was continued toreflux overnight. After cooled to room temperature, the reaction mixturewas diluted with ethyl acetate (100 mL), washed with Sat. NaHCO₃ andbrine, dried over sodium sulfate, and concentrated under reducedpressure. The resulting residue was purified by column chromatography(silica gel, petroleum ether/ethyl acetate: 20/1) to afford 10 g ofmethyl 5-(benzyloxycarbonylamino)bicyclo-[3.2.1]octane-1-carboxylate(containing BnOH) as a brown oil. ESI-MS m/z: 318 (M+H)⁺. It was used inthe next step without purification.

Step 6: 5-(benzyloxycarbonylamino)bicyclo[3.2.1]octane-1-carboxylic acid

To a solution of methyl5-(benzyloxycarbonylamino)bicyclo-[3.2.1]octane-1-carboxylate (25 g,crude product) in methanol (200 mL) was added NaOH (5N, 50 mL) and thereaction mixture was refluxed for two hours. After cooled to roomtemperature, the mixture was concentrated under reduced pressure. Theresidue was diluted with water (100 mL) and extracted with diethyl ether(3×100 mL) to remove the organic impurities. The aqueous phase wasadjusted to pH 1˜2 with 2N aq. HCl, and extracted with dichloromethane(3×100 mL). The combined organic layer was washed with brine, dried oversodium sulfate and concentrated under reduced pressure to afford 8.5 g(49%, steps 5 and 6) of5-(benzyloxycarbonylamino)bicyclo[3.2.1]octane-1-carboxylic acid as ayellow oil. ESI-MS m/z: 304 (M+H)⁺.

Step 7: Benzyl 5-aminobicyclo[3.2.1]octan-1-ylcarbamate

A mixture of 5-(benzyloxycarbonylamino)bicyclo[3.2.1]octane-1-carboxylicacid (8.5 g, 28.0 mmol), diphenylphosphonic azide (9.3 g, 33.8 mmol) andtriethylamine (5 mL, 68 mmol) in toluene (150 mL) was stirred at roomtemperature for one hour, and then refluxed for three hours. Aftercooled to 0° C., a solution of TMSOK (10.7 g, 83.6 mmol) in THF (85 mL)was added. The reaction mixture was warmed to room temperature andstirred for 1 h, and then quenched with 5% citric acid (20 mL) andconcentrated under reduced pressure. The residue was treated with aq.HCl (2 N, 200 mL) at 0° C. The resulting mixture was extracted withethyl acetate (3×100 mL). The aqueous phase was adjusted to pH 9˜10 withNa₂CO₃ and extracted with dichloromethane/methanol (10/1, 3×150 mL). Thecombined organic layer was washed with water and brine, dried oversodium sulfate and concentrated under reduced pressure to afford 5.13 g(42%) of benzyl 5-aminobicyclo[3.2.1]octan-1-ylcarbamate as a yellowsolid. ESI-MS m/z: 275 (M⁺+1).

Step 8: Benzyl (5-(3-fluorobenzamido)bicyclo[3.2.1]octan-1-yl)carbamate

To a solution of benzyl 5-aminobicyclo[3.2.1]octan-1-ylcarbamate (402mg, 1.47 mmol) and 3-fluorobenzoic acid (309 mg, 2.21 mmol) in DMF (20mL) was added HATU (1.12 g, 2.95 mmol) and DIPEA (1 mL). After stirringat room temperature for 1 hour, water (100 mL) was added and the mixturewas extracted with ethyl acetate (3×50 mL). The combined organic layerwas washed with brine, dried over Na₂SO₄, and concentrated under reducedpressure. The resulting residue was purified by column chromatography(silica gel, petroleum ether/ethyl acetate: 2/1) to give 513 mg (88%) ofbenzyl (5-(3-fluorobenzamido)bicyclo[3.2.1]octan-1-yl) carbamate as awhite solid. ESI-MS m/z: 397 (M+H)⁺.

Step 9: N-(5-aminobicyclo[3.2.1]octan-1-yl)-3-fluorobenzamide

To a solution of N-(5-aminobicyclo[3.2.1]octan-1-yl)-3-fluorobenzamide(513 mg, 1.30 mmol) in methanol (50 mL) was added Pd/C (10%, 100 mg) andthe reaction mixture was hydrogenated (1 atm) at room temperatureovernight. The reaction mixture was then filtered through a Celite pad,and the filtrate was concentrated under reduced pressure to affordN-(5-aminobicyclo[3.2.1]octan-1-yl)-3-fluorobenzamide (329 mg, 97%) as awhite solid. ESI-MS m/z: 263 (M+H)⁺.

Intermediate 4 6-Methyl-pyrazine-2-carboxylicacid(5-amino-bicyclo[3.2.1]oct-1-yl)-amide

Intermediate 4 (6.2 g) was prepared analogously to intermediate 3. ¹HNMR (500 MHz, CD₃OD): δ 8.87 (s, 1H), 8.56 (s, 1H), 2.51 (s, 3H),2.11-2.01 (m, 3H), 1.89-1.88 (m, 1H), 1.71-1.40 (m, 8H). ESI-MS m/z: 261(M+H)⁺.

Intermediate 5 N-(5-aminobicyclo[3.2.1]oct-1-yl)-3-chlorobenzamide

Intermediate 5 (2.3 g) was prepared analogously to intermediate 3. ¹HNMR (500 MHz, CDCl₃): δ 7.71 (s, 1H), 7.61 (d, J=2.5 Hz, 1H), 7.46 (d,J=2.0 Hz, 1H), 7.37-7.34 (m, 1H), 6.13 (s, 1H), 2.21-1.98 (m, 4H),1.79-1.52 (m, 10H). ESI-MS m/z: 279 (M+H)⁺.

Intermediate 6 N-(5-aminobicyclo[3.2.1]oct-1-yl)-3-methylbenzamide

Intermediate 6 (2.2 g) was prepared analogously to intermediate 3. ¹HNMR (500 MHz, CDCl₃): δ 7.54-7.50 (m, 2H), 7.22 (d, J=6.0 Hz, 2H), 6.78(s, 1H), 2.32 (s, 1H), 2.12-1.96 (m, 4H), 1.69-1.41 (m, 10H). ESI-MSm/z: 259 (M+H)⁺.

Intermediate 7N-(5-aminobicyclo[3.2.1]oct-1-yl)-5-fluoropyridine-2-carboxamide

Intermediate 7 (50 mg) was prepared analogously to intermediate 3.ESI-MS m/z: 264 (M+H)⁺.

Intermediate 8N-(5-aminobicyclo[3.2.1]oct-1-yl)-5-methylpyrazine-2-carboxamide

Intermediate 8 (500 mg) was prepared analogously to intermediate 3.ESI-MS m/z: 261 (M+H)⁺.

Intermediate 9 N-(5-aminobicyclo[3.2.1]oct-1-yl)pyrazine-2-carboxamide

Intermediate 9 (800 mg) was prepared analogously to intermediate 3. ¹HNMR (500 MHz, CDCl₃): δ 9.39 (d, J=1.0 Hz, 1H), 8.74 (d, J=2.0 Hz, 1H),8.50 (d, J=2.0 Hz, 1H), 7.88 (s, 1H), 2.27-1.97 (m, 4H), 1.82-1.70 (m,6H), 1.60-1.54 (m, 4H). ESI-MS m/z: 247 (M+H)⁴.

Intermediate 10 N-(5-aminobicyclo[3.2.1]oct-1-yl)pyridine-2-carboxamide

Intermediate 10 (2.8 g) was prepared analogously to intermediate 3. ¹HNMR (500 MHz, CDCl₃): δ 8.53-8.52 (m, 1H), 8.18-8.15 (m, 2H), 7.86-7.82(m, 1H), 7.42-7.40 (m, 1H), 2.28-1.97 (m, 4H), 1.80-1.55 (m, 10H).ESI-MS m/z: 246 (M+H)⁺.

Intermediate 11 6-Methyl-pyridine-2-carboxylic acid(5-amino-bicyclo[3.2.1]oct-1-yl)-amide

Intermediate 11 (3.2 g) was prepared analogously to intermediate 3. ¹HNMR (500 MHz, CDCl₃): δ 8.20 (s, 1H), 7.96 (d, =9.5 Hz, 1H), 7.69 (t,J=9.5 Hz, 1H), 7.26 (d, J=9.5 Hz, 1H), 2.56 (s, 3H), 2.28-1.96 (m, 4H),1.80-1.55 (m, 10H); ESI-MS m/z: 260 (M+H)⁺.

Intermediates 12 and 13{(1S,5R)-5-[(6-Methyl-pyrazine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-carbamicacid tert-butyl ester and{(1R,5S)-5-[(6-methyl-pyrazine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-carbamicacid tert-butyl ester

To a solution of 6-methyl-pyrazine-2-carboxylic acid(5-amino-bicyclo[3.2.1]oct-1-yl)-amide (intermediate 4, 1.15 g, 4.42mmol) in DCM (20.0 mL) was added triethylamine (1.23 mL, 8.83 mmol),followed by di-tert-butyldicarbonate (1.01 g, 4.64 mmol). After stirringat rt overnight, the reaction mixture was concentrated under reducedpressure. The residue was purified on the CombiFlash® system(hexane/ethyl acetate: 100/0 to 40/60 in 8 mins, then hexane/ethylacetate: 40/60) to afford 1.0 g (63%) of{5-[(6-methyl-pyrazine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-carbamicacid tert-butyl ester (ESI-MS m/z: 361 (M+H)⁺), which was then resolvedon a Supercritical Fluid Chromatography (SFC) preparative separationsystem (Column: 30×150 mm OJ-H (Chiral Technologies Inc). Solvent:isopropyl alcohol/CO₂: 5/95. Detector: UV at 250 nm. Flow rate: 100mL/min). The front peak was arbitrarily assigned as{(1S,5R)-5-[(Pyrazine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-carbamicacid tert-butyl ester (intermediate 12, 0.32 g, ESI-MS m/z: 361 (M+H)⁺)and the back peak was arbitrarily assigned as{(1R,5S)-5-[(pyrazine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-carbamicacid tert-butyl ester (intermediate 13, 0.33 g, ESI-MS m/z: 361 (M+H)⁺).

Intermediates 14 and 15{(1S,5R)-5-[(Pyrazine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-carbamicacid tert-butyl ester and{(1R,5S)-5-[(pyrazine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-carbamicacid tert-butyl ester

In an analogous manner to intermediates 12 and 13, intermediates 14(ESI-MS m/z: 347 (M+H)⁺) and 15 (ESI-MS m/z: 347 (M+H)⁺) were made from0.95 g of intermediate 9. The absolute stereochemistry of 14 and 15 werearbitrarily assigned.

Intermediates 16 and 17{(1S,5R)-5-[(6-Methyl-pyridine-2-carbonyl)-amino]bicyclo[3.2.1]oct-1-yl}-carbamicacid tert-butyl ester and{(1R,5S)-5-[(6-methyl-pyridine-2-carbonyl)-amino]bicyclo[3.2.1]oct-1-yl}-carbamicacid tert-butyl ester

In an analogous manner to intermediates 12 and 13, intermediates 16 (2.2g, ESI-MS m/z: 360 (M+H)⁺) and 17 (2.2 g, ESI-MS m/z: 360 (M+H)⁺) weremade from 5.2 g of intermediate 11. The absolute stereochemistry of 16and 17 were arbitrarily assigned.

Intermediates 18 and 19{(1S,5R)-5-[(Pyridine-2-carbonyl)amino]bicyclo[3.2.1]oct-1-yl}-carbamicacid tert-butyl ester and{(1R,5S)-5-[(pyridine-2-carbonyl)-amino]bicyclo[3.2.1]oct-1-yl}-carbamicacid tert-butyl ester

In an analogous manner to intermediates 12 and 13, intermediates 18 (1.2g, ESI-MS m/z: 346 (M+H)⁺) and 19 (1.25 g, ESI-MS m/z: 346 (M+H)⁺) weremade from 2.0 g of intermediate 10. The absolute stereochemistry of 16and 1.7 were arbitrarily assigned.

Intermediate 20 Pyrazine-2-carboxylic acid(1S,5R)-5-amino-bicyclo[3.2.1]oct-1-yl)-amide HCl salt

To a solution of{(1R,5S)-5-[(pyrazine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-carbamicacid ten-butyl ester (intermediate 15, 0.9 g, 2.6 mmol) in methylenechloride (5.0 mL) was added 4 M of hydrogen chloride in 1,4-dioxane (6.5mL). After stirring at room temperature overnight, the reaction mixturewas concentrated under reduced pressure to afford 0.7 g ofpyrazine-2-carboxylic acid((1S,5R)-5-amino-bicyclo[3.2.1]oct-1-yl)-amide HCl salt, which was usedin the next step without further purification. ESI-MS m/z: 247 (M+H)⁺.

Intermediate 21 6-Methyl-pyridine-2-carboxylic acid((1S,5R)-5-amino-bicyclo[3.2.1]oct-1-yl)-amide

In an analogous manner to intermediate 20, intermediate 21 (2.0 g,ESI-MS m/z: 260 (M+H)⁺) was prepared from intermediate 17 (2.5 g).

Intermediate 22 6-Methyl-pyridine-2-carboxylic acid((1R,5S)-5-amino-bicyclo[3.2.1]oct-1-yl)-amide

In an analogous manner to intermediate 20, intermediate 22 (1.36 g,ESI-MS m/z: 260 (M+H)⁺) was prepared from intermediate 16 (2.2 g).

Intermediate 23 Pyridine-2-carboxylic acid((1S,5R)-5-amino-bicyclo[3.2.1]oct-1-yl)-amide

In an analogous manner to intermediate 20, intermediate 23 (1.1 g,ESI-MS m/z: 246 (M+H)⁺) was prepared from intermediate 19 (1.25 g).

Intermediate 24 Pyridine-2-carboxylic acid((1R,5S)-5-amino-bicyclo[3.2.1]oct-1-yl)-amide

In an analogous manner to intermediate 20, intermediate 24 (1.05 g,ESI-MS m/z: 246 (M+H)⁺) was prepared from intermediate 18 (1.2 g).

Intermediate 25 6-Methyl-pyrazine-2-carboxylic acid((1S,5R)-5-amino-bicyclo[3.2.1]oct-1-yl)-amide HCl salt

In an analogous manner to intermediate 20, intermediate 25 (1.2 g,ESI-MS m/z: 261 (M+H)⁺) was prepared from intermediate 13 (1.5 g).

Intermediate 265-(6-Methylpyrazine-2-carboxamido)bicyclo[3.2.1]octane-1-carboxylic acid

Intermediate 26 was prepared via the processes of Scheme 8, supra, asfollows:

Step 1: Methyl 5-aminobicyclo[3.2.1]octane-1-carboxylate

To a solution of methyl5-(benzyloxycarbonylamino)bicyclo-[3.2.1]octane-1-carboxylate (10 g) inmethanol (150 mL) was added 10% Pd/C (1 g) and the reaction mixture wasstirred under H₂ (1 atm) at room temperature overnight. The reactionmixture was filtered through a Celite pad, and the filtrate wasconcentrated. The residue was treated with aqueous HCl (2N, 200 mL) at0° C. and then extracted with ethyl acetate (3×100 mL) to remove organicimpurities. The aqueous phase was adjusted to pH 9-10 with Sat. Na₂CO₃and extracted with dichloromethane/methanol (10/1, 3×100 mL). Thecombined organic layer was washed with water (100 mL) and brine (100mL), dried over sodium sulfate and concentrated under reduced pressureto afford 2.98 g of methyl 5-aminobicyclo[3.2.1]octane-1-carboxylate asa yellow oil. ESI-MS m/z: 184 (M+H)⁺.

Step 2: methyl5-(6-methylpyrazine-2-carboxamido)bicyclo[3.2.1]octane-1-carboxylate

To a solution of methyl 5-aminobicyclo[3.2.1]octane-1-carboxylate (0.98g, 5.36 mmol) and 6-methylpyrazine-2-carboxylic acid (0.89 g, 6.45 mmol)in DCM (30 mL) and TEA (2 mL) was added PyBOP (3.35 g, 6.44 mmol). Afterstirring at room temperature overnight, water (30 mL) was added and themixture was extracted with DCM (3×50 mL). The combined organic layer waswashed with Sat. NaHCO₃ (50 mL) and brine (50 mL), dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by columnchromatography (silica gel, petroleum ether/ethyl acetate: 1/1) toafford 1.28 g (79%) of methyl5-(6-methylpyrazine-2-carboxamido)bicyclo[3.2.1]octane-1-carboxylate asan off-white solid. ESI-MS m/z: 304 (M+H)⁺.

Step 3:5-(6-methylpyrazine-2-carboxamido)bicyclo[3.2.1]octane-1-carboxylic acid

A solution of methyl5-(6-methylpyrazine-2-carboxamido)bicyclo[3.2.1]octane-1-carboxylate(1.28 g, 4.21 mmol) and LiOH (0.15 g, 6.25 mmol) in methanol (30 mL) andH₂O (3 mL) was refluxed for two hours. After cooled to room temperature,methanol was removed under reduced pressure. The residue was partitionedbetween water (50 mL) and diethyl ether (50 mL) to remove organicimpurities. The aqueous phase was adjusted to pH 1˜2 with 2N aq. HCl andthen extracted with dichloromethane (3×50 mL). The combined organiclayer was washed with water (50 mL) and brine (50 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford 1.11 g (91%) of5-(6-methylpyrazine-2-carboxamido)bicyclo[3.2.1]octane-1-carboxylic acidas a white solid. ESI-MS m/z: 290 (M+H)⁺.

Intermediate 275-amino-N-(2-methylpyrimidin-4-yl)bicyclo[3.2.1]octane-1-carboxamide

Intermediate 27 was prepared via the processes of Scheme 9, supra, asfollows:

Step 1: 5-(benzyloxycarbonylamino)bicyclo[3.2.1]octane-1-carboxylic acid

To a solution of5-(benzyloxycarbonylamino)bicyclo-[3.2.1]octane-1-carboxylate (10 g,31.5 mmol) in MeOH (150 mL) was added NaOH (2N, 50 mL) and the reactionsolution was stirred at room temperature overnight. The organic solventwas removed under reduced pressure and the remaining aqueous solutionwas extracted with ethyl acetate (20 mL) to remove the organicimpurities, and then adjusted to pH 3 with 2N aq. HCl. The acidicaqueous solution was extracted with ethyl acetate (3×20 mL) and thecombined organic layer was washed with brine, dried over Na₂SO₄ andconcentrated to give 9 g (95%)5-(benzyloxycarbonylamino)bicyclo[3.2.1]octane-1-carboxylic acid as acolorless oil, which was solidified after standing at room temperatureovernight. ESI-MS m/z: 304 (M+H)⁺.

Step 2: Benzyl 5-carbamoylbicyclo[3.2.1]octan-1-ylcarbamate

To a solution of5-(benzyloxycarbonylamino)bicyclo[3.2.1]octane-1-carboxylic acid (1.0 g,3.3 mmol) in DCM (30 mL) was added dropwise oxalyl chloride (5 mL),followed by two or three drops of DMF. After stirring at roomtemperature for an hour, the reaction mixture was concentrated underreduced pressure. The resulting residue was dissolved in THF (30 mL) andthe solution was bubbled with NH₃ (gas). A white solid crashed out andthe reaction mixture was continued to stir for half an hour. Afterquenched with brine (20 mL), the mixture was extracted with ethylacetate (3×20 mL). The combined organic layer was washed with brine,dried over Na₂SO₄ and concentrated under reduced pressure to afford 1 g(100%) of benzyl 5-carbamoylbicyclo[3.2.1]octan-1-ylcarbamate as acolorless oil, which was used in the next step without purification.ESI-MS m/z: 303 (M+H)⁺.

Step 3: Benzyl5-(2-methylpyrimidin-4-ylcarbamoyl)bicyclo[3.2.1]octan-1-ylcarbamate

To a mixture of benzyl 5-carbamoylbicyclo[3.2.1]octan-1-ylcarbamate (1g, 3.3 mmol) and Cs₂CO₃ (1.6 g, 4.9 mmol) and BINAP (200 mg, 0.3 mmol)in toluene (60 mL), was added 4-chloro-2-methylpyrimidine (430 mg, 3.3mmol), followed by Pd₂(dba)₃ (300 mg, 0.32 mmol). The mixture wasstirred at 100° C. under N₂ overnight. After cooled to room temperature,the reaction mixture was concentrated under reduced pressure and theresulting residue was purified by column chromatography (silica gel,petroleum ether/ethyl acetate: 4/1) to give 1 g (77%) of benzyl5-(2-methylpyrimidin-4-ylcarbamoyl)bicyclo[3.2.1]octan-1-ylcarbamate asa light yellow oil. ESI-MS m/z: 395 (M+H)⁺.

Step 4:5-amino-N-(2-methylpyrimidin-4-yl)bicyclo[3.2.1]octane-1-carboxamide

A solution of benzyl5-(2-methylpyrimidin-4-ylcarbamoyl)bicyclo[3.2.1]octan-1-ylcarbamate (1g, 2.5 mmol) in HBr/HOAc (33% solution, 8 mL) was stirred at roomtemperature for an hour and then concentrated under reduced pressure.The resulting residue was dissolved in aq. HCl (6N, 10 mL) and extractedwith ethyl acetate (10 mL) to remove the organic impurities. The aqueousphase was basified with aq. NaOH (6N, 4 mL), and then extracted with DCM(4×20 mL). The combined organic layer was washed with brine, dried overNa₂SO₄ and concentrated under reduced pressure to afford 350 mg (66%) of5-amino-N-(2-methylpyrimidin-4-yl)bicyclo[3.2.1]octane-1-carboxamide asa white solid ESI-MS m/z: 261 (M+H)⁺.

Intermediate 285-amino-N-(6-methylpyrazin-2-yl)bicyclo[3.2.1]octane-1-carboxamide

In an analogous manner to intermediate 27, 520 mg of intermediate 28 wasmade. ESI-MS m/z: 261 (M+H)⁺.

Intermediate 29 5-amino-N-pyridin-3-ylbicyclo[3.2.1]octane-1-carboxamide

In an analogous manner to intermediate 27, 175 mg of intermediate 29 wasmade. ESI-MS m/z: 246 (M+H)⁺.

Intermediate 30 5-amino-N-pyrazin-2-ylbicyclo[3.2.1]octane-1-carboxamide

In an analogous manner to intermediate 27, 110 mg of intermediate 30 wasmade. ESI-MS m/z: 247 (M+H)⁺.

Intermediate 315-amino-N-(6-methylpyridin-2-yl)bicyclo[3.2.1]octane-1-carboxamide

In an analogous manner to intermediate 27, 530 mg of intermediate 31 wasmade. ESI-MS m/z: 260 (M+H)⁺.

3. Preparation of Compounds of the Invention

Unless specified otherwise, all starting materials and reagents wereobtained from commercial suppliers, such as Sigma-Aldrich Corp. (St.Louis, Mo., USA) and its subsidiaries, and used without furtherpurification.

Example 1 N,N′-(bicyclo[3.2.1]octane-1,5-diyl)dipicolinamide

Example 1 of Table 1 was prepared from intermediate 1 via the process ofScheme 1, supra, as follows:

A mixture of bicyclo[3.2.1]octane-1,5-diamine dihydrochloride (20 mg,0.094 mmol) and picolinic acid (34.6 mg, 0.28 mmol) in methylenechloride (6 mL) was treated with triethylamine (0.13 mL, 0.94 mmol). Themixture was stirred at rt for a few minutes.N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (72.0 mg,0.38 mmol) and 4-dimethylaminopyridine (2.3 mg, 0.02 mmol) were added.The reaction was stirred at rt overnight. The reaction was diluted witha small amount of dichloromethane and washed with water. The organiclayer was collected, dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure. The resulting residue was purifiedwith chromatography to give 5.4 mg (16%) of the desired product.Analytical data were listed in Table 3.

Example 2 and 3N-(5-(3-chlorobenzamido)bicyclo[3.2.1]octan-1-yl)-6-methylpicolinamideand N,N′-(bicyclo[3.2.1]octane-1,5-diyl)bis(6-methylpicolinamide)

Example 2 and 3 of Table 1 were prepared from intermediate 1 via theprocess of Scheme 2, supra, as follows:

A mixture of bicyclo[3.2.1]octane-1,5-diamine dihydrochloride (100 mg,0.469 mmol), 6-methylpicolinic acid (64.3 mg, 0.47 mmol) and3-chloro-benzoic acid (73.4 mg, 0.47 mmol) in methylene chloride (10 mL,200 mmol) was treated with triethylamine (0.66 mL, 4.69 mmol). Themixture was stirred for a few minutes.N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (360 mg,1.88 mmol) and 4-dimethylaminopyridine (11.5 mg, 0.0938 mmol) wereadded. The reaction mixture was stirred at rt overnight. The reactionwas diluted with a small amount of dichloromethane and washed withwater. The organic layer was dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure. The crude materialwas purified on a reversed phase liquid chromatography/mass spectrometry(RP-HPLC/MS) purification system (Gradient: acetonitrile in water,25-95% in 3.6 minutes with a cycle time of 5 min. A shallow gradient of30-58% of acetonitrile was used between 0.75-3.6 min to separateclose-eluting impurities. Flow rate: 100 mL/min. Mobile phase additive:48 mM of ammonium formate. Column: Inertsil® C18, 30×50 mm, 5 umparticle size) to afford 3.0 mg (2%) of 6-methyl-pyridine-2-carboxylicacid [5-(3-chloro-benzoylamino)-bicyclo[3.2.1]oct-1-yl]-amide (Example2) and 7.0 mg (4%) ofN,N′-(bicyclo[3.2.1]octane-1,5-diyl)bis(6-methylpicolinamide) (Example3). Analytical data were listed in Table 3.

Example 4 6-Methyl-pyrazine-2-carboxylic acid{5-[(pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide

Example 4 of Table 1 was prepared from intermediate 2 via the process ofScheme 3, supra, as follows:

A mixture of 6-methyl-pyrazine-2-carboxylic acid(5-amino-bicyclo[3.2.1]oct-1-yl)-amide.ClH (15 mg, 0.05 mmol), picolinicacid (6.2 mg, 0.05 mmol),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(22.4 mg, 0.05 mmol) and triethylamine (0.02 mL, 0.15 mmol) in methylenechloride (2.0 mL) was stirred at rt for 2 hours. The mixture wasconcentrated under reduced pressure, and the resulting residue waspurified on a reversed phase liquid chromatography/mass spectrometry(RP-HPLC/MS) purification system (Gradient: acetonitrile in water,19-95% in 3.5 minutes with a cycle time of 5 min. A shallow gradientbetween 25-48% of acetonitrile was used between 0.65-3.2 min to separateclose-eluting impurities. Flow rate: 100 mL/min. Mobile phase additive:48 mM of ammonium formate. Column: Inertsil® C18, 30×50 mm, 5 minparticle size (GL Sciences)) to afford 8 mg (40%) of the desiredproduct. Analytical data were listed in Table 3.

In an analogous manner to Examples 4, Examples 5-8 of Table 1 were madefrom commercially available 6-methyl-pyrazine-2-carboxylic acid,3-fluoro-benzoic acid, 4-fluoro-benzoic acid and2-methyl-pyrimidine-4-carboxylic acid at 0.05-2 mmol reaction scales.Analytical data were listed in Table 3.

Example 98N-(5-(3-methylbenzamido)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide

Example 98 of Table 1 was prepared from intermediate 9 via the processof Scheme 3, supra, as follows:

To a solution of intermediate 9 (25 mg, 0.11 mmol) and 3-methylbenzoicacid (23 mg, 0.15 mmol) in DMF (5 mL) was added DIPEA (78 mg, 0.66 mmol)and HATU (54 mg, 0.15 mmol). After stirring at room temperature for onehour, water (20 mL) was added and the solution was extracted with ethylacetate (3×20 mL). The combined organic layer was washed with brine,dried over Na₂SO₄, and concentrated under reduced pressure. Theresulting residue was purified on a reversed phase liquidchromatography/mass spectrometry (RP-HPLC/MS) purification system(Mobile phase: A) 10 mM NH₄HCO₃ in water; B) acetonitrile. Gradient:32-37% B in 17 min, 37-95% B in 0.2 min, then hold at 95% B for 4 min,back to 10% B in 0.2 min, stop at 24 min. Flow rate: 30 mL/min. Column:Shimadzu pre-ods 20×250 mm, 15 μm, two connected in series) to afford 10mg (27%) ofN-(5-(3-methylbenzamido)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamideas a white solid. Analytical data were listed in Table 3.

In an analogous manner to example 98, examples 9-19, 20-34, 35-48,49-51, 52-64, 65-79, 80-93, 94-103 and 104-115 of Table 1 were made at0.1-2 mmol reaction scales from commercially available carboxylic acidsand amine intermediates 5, 3, 4, 6, 7, 8, 4, 11, 9 and 10 with yieldranging from 20-80%, respectively. Analytical data were listed in Table3.

In an analogous manner to example 4, examples 116-121, 122-131, 141-150and 151-155 of Table 1 were made at 0.1-1 mmol from commerciallyavailable carboxylic acids and chiral amine intermediates 22, 21, 23 and25 with yield ranging from 40-70%, respectively. The absolutestereochemistry of these compounds was arbitrarily assigned. Analyticaldata were listed in Table 3.

Example 133 6-Methyl-pyrazine-2-carboxylic acid{(1S,5R)-5-[(4-methyl-thiazole-2-carbonyl)-amino]bicyclo[3.2.1]oct-1-yl}-amide

To a solution of{(1R,5S)-5-[(6-methyl-pyrazine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-carbamicacid tert-butyl ester (intermediate 13, 0.050 g, 0.14 mmol) in 1 mL ofmethylene chloride, 4 M of hydrogen chloride in 1,4-dioxane (0.5 mL) wasadded. After stirring at rt overnight, the reaction mixture wasconcentrated under reduced pressure to dryness. The resulting residuewas dissolved in methylene chloride (1.0 mL),4-methyl-1,3-thiazole-2-carboxylic acid (19.8 mg, 0.14 mmol),triethylamine (7.73 μL, 0.56 mmol) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(61.4 mg, 0.14 mmol) were added. After stirring at rt for 1 hour, thereaction mixture was concentrated under reduced pressure. The resultingresidue was purified on the CombiFlash® system (hexane/ethyl acetate:100/0 to 10/90 in 10 mins, then hexane/ethyl acetate: 10/90) to afford31 mg (58%) of 6-methyl-pyrazine-2-carboxylic acid{(1S,5R)-5-[(4-methyl-thiazole-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide.Analytical data are listed in Table 3.

In an analogous manner to example 133, examples 132, 134 and 135 ofTable 1 were made at ˜0.15 mmol reaction scale from intermediate 13 andcommercially available carboxylic acids with yield ˜60%; examples136-140 of Table 1 were made at ˜0.15 mmol reaction scale fromintermediate 12 and commercially available carboxylic acids with yield˜60%. Analytical data were listed in Table 3.

Examples 158 and 159 6-Methyl-pyrazine-2-carboxylic acid{(1R,5S)-5-[(pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amideand 6-methyl-pyrazine-2-carboxylic acid{(1S,5R)-5-[(pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide

Example 8 (0.37 g, 1.0 mmol) was resolved on a chiral HPLC system(column: 30×150 mm OJ (Chiral Technologies Inc). Solvent: EtOH/hexane:10/90. Detector: UV at 290 nm. Flow rate: 14 mL/min). The front peak wasarbitrarily assigned as 6-methyl-pyrazine-2-carboxylic acid{(1R,5S)-5-[(pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide(example 158, 56 mg) and the back peak was arbitrarily assigned as6-methyl-pyrazine-2-carboxylic acid{(1S,5R)-5-[(pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide(example 159, 81 mg).

Similarly, examples 156 (31 mg) and 157 (33 mg) of Table 1 were obtainedby resolution of example 8, examples 160 (90 mg) and 161 (90 mg) ofTable 1 were obtained by resolution of example 6, and examples 162 (50mg) and 163 (66 mg) of Table 1 were obtained by resolution of example99, respectively. Analytical data were listed in Table 3.

Example 1646-methyl-N-{5-[(pyridin-2-ylamino)carbonyl]bicyclo[3.2.1]oct-1-yl}pyrazine-2-carboxamide

Example 164 of Table 2 was prepared from intermediate 26 via the processof Scheme 4, supra, as follows:

To a solution of5-(6-methylpyrazine-2-carboxamido)bicyclo[3.2.1]octane-1-carboxylic acid(intermediate 26, 100 mg, 0.35 mmol) and pyridin-2-amine (39 mg, 0.41mmol) in DMF (5 mL) was added HATU (158 mg, 0.41 mmol) and DIPEA (0.5mL). After stirring at room temperature for one hour, water (20 mL) wasadded, and the solution was extracted with ethyl acetate (3×20 mL). Thecombined organic layer was washed with brine, dried over Na₂SO₄, andconcentrated under reduced pressure. The resulting residue was purifiedby column chromatography (silica gel, petroleum ether/ethyl acetate:2/1) to yield 35 mg (27%) of6-methyl-N-{5-[(pyridin-2-ylamino)carbonyl]bicyclo[3.2.1]oct-1-yl}pyrazine-2-carboxamideas a white solid. Analytical data were listed in Table 3.

In an analogous manner to example 164, 165-168 of Table 2 was made fromintermediate 26 and commercially available heteroaryl amines at ˜0.3-0.6mmol reaction scales. Analytical data were listed in Table 3.

Using the procedure described in the preparation of example 98, examples169-177, 178-182, 183-185, 186 and 187 of Table 2 were synthesized fromcommercially available carboxylic acids and amine intermediates 31, 27,28, 29 and 30, respectively. Analytical data were listed in Table 3.

TABLE 1 Compounds of formula (I-A) Ex- ample No. Structure Chemical Name 1

N,N-bicyclo[3.2.1]octane-1,5- diyl)dipicolinamide  2

6-Methyl-pyridine-2-carboxylic acid [5- (3-chloro-benzoylamino)-bicyclo[3.2.1]oct-1-yl]-amide  3

N,N-bicyclo[3.2.1]octane-1,5-diyl)bis(6- methylpicolinamide)  4

6-Methyl-pyrazine-2-carboxylic acid {5- [(pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide  5

N,N-(bicyclo[3.2.1]octane-1,5- diyl)bis(6-methylpyrazine-2- carboxamide) 6

6-Methyl-pyrazine-2-carboxylic acid [5- (3-fluoro-benzoylamino)-bicyclo[3.2.1]oct-1-yl]-amide  7

6-Methyl-pyrazine-2-carboxylic acid [5- (4-fluoro-benzoylamino)-bicyclo[3.2.1]oct-1-yl]-amide  8

2-Methyl-pyrimidine-4-carboxylic acid{5-[(6-methyl-pyrazine-2-carbonyl)- amino]-bicyclo[3.2.1]oct-1-yl}-amide 9

N-(5-(3- chlorobenzamido)bicyclo[3.2.1]octan-1-yl)-4-methylpyrimidine-2-carboxamide  10

N-(5-(3- chlorobenzamido)bicyclo[3.2.1]octan-1-yl)pyrimidine-2-carboxamide  11

N-(5-(3- chlorobenzamido)bicyclo[3.2.1]octan-1-yl)pyrimidine-4-carboxamide  12

N-(5-(3- chlorobenzamido)bicyclo[3.2.1]octan-1-yl)thiazole-2-carboxamide  13

N-(5-(3- chlorobenzamido)bicyclo[3.2.1]octan-1-yl)-2-methylpyrimidine-4-carboxamide  14

N-(5-(3- chlorobenzamido)bicyclo[3.2.1]octan-1-yl)-4-methylthiazole-2-carboxamide  15

N-(5-(3- chlorobenzamido)bicyclo[3.2.1]octan-1-yl)-2-methylthiazole-5-carboxamide  16

N-(5-(3- chlorobenzamido)bicyclo[3.2.1]octan-1- yl)-5-fluoropicolinamide 17

N-(5-(3- chlorobenzamido)bicyclo[3.2.1]octan-1- yl)-5-methylpicolinamide 18

N-(5-(3- chlorobenzamido)bicyclo[3.2.1]octan-1- yl)-4-methylpicolinamide 19

N-(5-(3- chlorobenzamido)bicyclo[3.2.1]octan-1- yl)-5-methylnicotinamide 20

N-(5-(3- fluorobenzamido)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide  21

N-(5-(3- fluorobenzamido)bicyclo[3.2.1]octan-1- yl)picolinamide  22

N-(5-(3- fluorobenzamido)bicyclo[3.2.1]octan-1- yl)isonicotinamide  23

N-(5-(3- fluorobenzamido)bicyclo[3.2.1]octan-1- yl)-5-methylpicolinamide 24

N-(5-(3- fluorobenzamido)bicyclo[3.2.1]octan-1- yl)-6-methylpicolinamide 25

N-(5-(3- fluorobenzamido)bicyclo[3.2.1]octan-1-yl)-2-methylpyrimidine-4-carboxamide  26

N-(5-(3- fluorobenzamido)bicyclo[3.2.1]octan-1- yl)nicotinamide  27

N-{5-[(3- fluorobenzoyl)amino]bicyclo[3.2.1]oct-1-yl}pyrimidine-2-carboxamide  28

N-(5-(3- fluorobenzamido)bicyclo[3.2.1]octan-1-yl)-4-methylpyrimidine-2-carboxamide  29

N-(5-(3- fluorobenzamido)bicyclo[3.2.1]octan-1-yl)-4-methylthiazole-2-carboxamide  30

N-(5-(3- fluorobenzamido)bicyclo[3.2.1]octan-1-yl)-2-methylthiazole-5-carboxamide  31

N-(5-(3- fluorobenzamido)bicyclo[3.2.1]octan-1- yl)-4-methylpicolinamide 32

N-(5-(3- fluorobenzamido)bicyclo[3.2.1]octan-1- yl)-5-methylnicotinamide 33

N-(5-(3- fluorobenzamido)bicyclo[3.2.1]octan-1-yl)pyrimidine-4-carboxamide  34

N-(5-(3- fluorobenzamido)bicyclo[3.2.1]octan-1-yl)thiazole-2-carboxamide  35

N-(5-(3- methylbenzamido)bicyclo[3.2.1]octan-1- yl)nicotinamide  36

N-(5-(3- methylbenzamido)bicyclo[3.2.1]octan-1- yl)isonicotinamide  37

6-methyl-N-(5-(3- methylbenzamido)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide  38

4-methyl-N-(5-(3- methylbenzamido)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide  39

5-methyl-N-(5-(3- methylbenzamido)bicyclo[3.2.1]octan-1- yl)nicotinamide 40

N-(5-(3- methylbenzamido)bicyclo[3.2.1]octan-1-yl)pyrimidine-2-carboxamide  41

N-(5-(3- methylbenzamido)bicyclo[3.2.1]octan-1-yl)pyrimidine-4-carboxamide  42

N-(5-(3- methylbenzamido)bicyclo[3.2.1]octan-1-yl)thiazole-4-carboxamide  43

2-methyl-N-(5-(3- methylbenzamido)bicyclo[3.2.1]octan-1-yl)pyrimidine-4-carboxamide  44

4-methyl-N-(5-(3- methylbenzamido)bicyclo[3.2.1]octan-1-yl)thiazole-2-carboxamide  45

2-methyl-N-(5-(3- methylbenzamido)bicyclo[3.2.1]octan-1-yl)thiazole-5-carboxamide  46

5-fluoro-N-(5-(3- methylbenzamido)bicyclo[3.2.1]octan-1- yl)picolinamide 47

5-methyl-N-(5-(3- methylbenzamido)bicyclo[3.2.1]octan-1- yl)picolinamide 48

4-methyl-N-(5-(3- methylbenzamido)bicyclo[3.2.1]octan-1- yl)picolinamide 49

N-(5-(5- fluoropicolinamido)bicyclo[3.2.1]octan-1-yl)-2-methylpyrimidine-4- carboxamide  50

5-fluoro-N-(5-(6- methylpicolinamido)bicyclo[3.2.1]octan-1-yl)picolinamide  51

N-(5-(5- fluoropicolinamido)bicyclo[3.2.1]octan-1-yl)-6-methylpyrazine-2-carboxamide  52

5-methyl-N-(5-(6-methylpyrazine-2- carboxamido)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide  53

5-methyl-N-(5-(3- methylbenzamido)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide  54

N-(5-(3- fluorobenzamido)bicyclo[3.2.1]octan-1-yl)-5-methylpyrazine-2-carboxamide  55

N-(5-(3- chlorobenzamido)bicyclo[3.2.1]octan-1-yl)-5-methylpyrazine-2-carboxamide  56

N-(5-{[(5-methylpyrazin-2- yl)carbonyl]amino}bicyclo[3.2.1]oct-1-yl)pyrimidine-4-carboxamide  57

N-(5-(5-methylpyrazine-2- carboxamido)bicyclo[3.2.1]octan-1-yl)thiazole-2-carboxamide  58

N-(5-benzamidobicyclo[3.2.1]octan-1- yl)-5-methylpyrazine-2-carboxamide 59

4-methyl-N-(5-(5-methylpyrazine-2- carboxamido)bicyclo[3.2.1]octan-1-yl)pyrimidine-2-carboxamide  60

2-methyl-N-(5-(5-methylpyrazine-2- carboxamido)bicyclo[3.2.1]octan-1-yl)pyrimidine-4-carboxamide  61

5-methyl-N-(5-{[(4-methyl-1,3-thiazol-2-yl)carbonyl]amino}bicyclo[3.2.1]oct- 1-yl)pyrazine-2-carboxamide  62

N-(5-{[(5-fluoropyridin-2- yl)carbonyl]amino}bicyclo[3.2.1]oct-1-yl)-5-methylpyrazine-2-carboxamide  63

5-methyl-N-(5-(5- methylpicolinamido)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide  64

5-methyl-N-(5-(4- methylpicolinamido)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide  65

N-(5-(3-fluoro-6- methylpicolinamido)bicyclo[3.2.1]octan-1-yl)-6-methylpyrazine-2-carboxamide  66

N-(5-(2- fluorobenzamido)bicyclo[3.2.1]octan-1-yl)-6-methylpyrazine-2-carboxamide  67

N-(5-(3,5- difluorobenzamido)bicyclo[3.2.1]octan-1-yl)-6-methylpyrazine-2-carboxamide  68

6-methyl-N-(5- (nicotinamido)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide  69

N-(5-(3- chlorobenzamido)bicyclo[3.2.1]octan-1-yl)-6-methylpyrazine-2-carboxamide  70

4-methyl-N-(5-(6-methylpyrazine-2- carboxamido)bicyclo[3.2.1]octan-1-yl)pyrimidine-2-carboxamide  71

N-(5-(6-methylpyrazine-2- carboxamido)bicyclo[3.2.1]octan-1-yl)pyrimidine-4-carboxamide  72

N-(5-(6-methylpyrazine-2- carboxamido)bicyclo[3.2.1]octan-1-yl)thiazole-2-carboxamide  73

N-(5-benzamidobicyclo[3.2.1]octan-1- yl)-6-methylpyrazine-2-carboxamide 74

4-methyl-N-(5-(6-methylpyrazine-2- carboxamido)bicyclo[3.2.1]octan-1-yl)thiazole-2-carboxamide  75

6-methyl-N-(5-(5- methylpicolinamido)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide  76

6-methyl-N-(5-(4- methylpicolinamido)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide  77

6-methyl-N-(5-(5- methylnicotinamido)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide  78

6-methyl-N-(5-(pyrazine-2- carboxamido)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide  79

N-(5-(6-methylpyrazine-2- carboxamido)bicyclo[3.2.1]octan-1-yl)pyrimidine-2-carboxamide  80

6-methyl-N-(5-(6- methylpicolinamido)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide  81

6-methyl-N-(5-(5- methylnicotinamido)bicyclo[3.2.1]octan-1-yl)picolinamide  82

6-methyl-N-(5-(3- methylbenzamido)bicyclo[3.2.1]octan-1- yl)picolinamide 83

N-(5-(6- methylpicolinamido)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide  84

N-(5-(6- methylpicolinamido)bicyclo[3.2.1]octan-1-yl)pyrimidine-2-carboxamide  85

N-(5-(6- methylpicolinamido)bicyclo[3.2.1]octan-1-yl)pyrimidine-4-carboxamide  86

N-(5-(6- methylpicolinamido)bicyclo[3.2.1]octan-1-yl)thiazole-2-carboxamide  87

N-(5-benzamidobicyclo[3.2.1]octan-1- yl)-6-methylpicolinamide  88

5-methyl-N-(5-(6- methylpicolinamido)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide  89

4-methyl-N-(5-(6- methylpicolinamido)bicyclo[3.2.1]octan-1-yl)pyrimidine-2-carboxamide  90

2-methyl-N-(5-(6- methylpicolinamido)bicyclo[3.2.1]octan-1-yl)pyrimidine-4-carboxamide  91

2-methyl-N-(5-(6- methylpicolinamido)bicyclo[3.2.1]octan-1-yl)thiazole-5-carboxamide  92

6-methyl-N-(5-(5- methylpicolinamido)bicyclo[3.2.1]octan-1-yl)picolinamide  93

6-methyl-N-(5-(4- methylpicolinamido)bicyclo[3.2.1]octan-1-yl)picolinamide  94

N-(5-(3-fluoro-6- methylpicolinamido)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide  95

Pyrazine-2-carboxylic acid [5-(3- trifluoromethyl-benzoylamino)-bicyclo[3.2.1]oct-1-yl]-amide  96

Pyrazine-2-carboxylic acid [5-(3-cyano-benzoylamino)-bicyclo[3.2.1]oct-1-yl]- amide  97

Pyrazine-2-carboxylic acid {5-[(3- fluoro-pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide  98

N-(5-(3- methylbenzamido)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide  99

N-(5-(3- chlorobenzamido)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide 100

2-methyl-N-(5-(pyrazine-2- carboxamido)bicyclo[3.2.1]octan-1-yl)pyrimidine-4-carboxamide 101

4-methyl-N-(5-(pyrazine-2- carboxamido)bicyclo[3.2.1]octan-1-yl)thiazole-2-carboxamide 102

N-(5-(5- fluoropicolinamido)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide 103

N-(5-(4- methylpicolinamido)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide 104

2-methyl-N-(5- (picolinamido)bicyclo[3.2.1]octan-1-yl)pyrimidine-4-carboxamide 105

6-methyl-N-(5- (picolinamido)bicyclo[3.2.1]octan-1- yl)picolinamide 106

5-methyl-N-(5- (picolinamido)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide 107

4-methyl-N-(5- (picolinamido)bicyclo[3.2.1]octan-1-yl)pyrimidine-2-carboxamide 108

4-methyl-N-(5- (picolinamido)bicyclo[3.2.1]octan-1-yl)thiazole-2-carboxamide 109

2-methyl-N-(5- (picolinamido)bicyclo[3.2.1]octan-1-yl)thiazole-5-carboxamide 110

5-fluoro-N-(5- (picolinamido)bicyclo[3.2.1]octan-1- yl)picolinamide 111

5-methyl-N-(5- (picolinamido)bicyclo[3.2.1]octan-1- yl)picolinamide 112

4-methyl-N-(5- (picolinamido)bicyclo[3.2.1]octan-1- yl)picolinamide 113

N-(5-(5- methylnicotinamido)bicyclo[3.2.1]octan- 1-yl)picolinamide 114

N-(5-(3- methylbenzamido)bicyclo[3.2.1]octan-1- yl)picolinamide 115

N-(5-(3- chlorobenzamido)bicyclo[3.2.1]octan-1- yl)picolinamide 116

3-Fluoro-6-methyl-pyridine-2-carboxylic acid{(1S,5R)-5-[(6-methyl-pyridine-2- carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide 117

6-Methyl-pyridine-2-carboxylic acid [(1R,5S)-5-(3-fluoro-benzoylamino)-bicyclo[3.2.1]oct-1-yl]-amide 118

6-Methyl-pyridine-2-carboxylic acid [(1R,5S)-5-(3-methyl-benzoylamino)-bicyclo[3.2.1]oct-1-yl]-amide 119

6-Methyl-pyridine-2-carboxylic acid {(1R,5S)-5-[(pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide 120

2-Methyl-pyrimidine-4-carboxylic acid {(1S,5R)-5-[(6-methyl-pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1- yl}-amide 121

Pyrimidine-4-carboxylic acid {(1S,5R)-5-[(6-methyl-pyridine-2-carbonyl)- amino]-bicyclo[3.2.1]oct-1-yl}-amide122

6-Methyl-pyridine-2-carboxylic acid ((1S,5R)-5-benzoylamino-bicyclo[3.2.1]oct-1-yl)-amide 123

3-Fluoro-6-methyl-pyridine-2-carboxylic acid{(1R,5S)-5-[(6-methyl-pyridine-2- carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide 124

2-Methyl-pyrimidine-4-carboxylic acid {(1R,5S)-5-[(6-methyl-pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1- yl}-amide 125

6-Methyl-pyridine-2-carboxylic acid [(1S,5R)-5-(3-fluoro-benzoylamino)-bicyclo[3.2.1]oct-1-yl]-amide 126

6-Methyl-pyridine-2-carboxylic acid {(1S,5R)-5-[(pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide 127

Pyrimidine-4-carboxylic acid {(1R,5S)-5-[(6-methyl-pyridine-2-carbonyl)- amino]-bicyclo[3.2.1]oct-1-yl}-amide128

5-fluoro-N-((1R,5S)-5-(6- methylpicolinamido)bicyclo[3.2.1]octan-1-yl)picolinamide 129

6-Methyl-pyridine-2-carboxylic acid {(1S,5R)-5-[(thiazole-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide 130

6-methyl-N-((1R,5S)-5-(4- methylpicolinamido)bicyclo[3.2.1]octan-1-yl)picolinamide 131

5-methoxy-N-((1R,5S)-5-(6- methylpicolinamido)bicyclo[3.2.1]octan-1-yl)picolinamide 132

6-Methyl-pyrazine-2-carboxylic acid {(1S,5R)-5-[(6-methyl-pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1- yl}-amide 133

6-Methyl-pyrazine-2-carboxylic acid {(1S,5R)-5-[(4-methyl-thiazole-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1- yl}-amide 134

6-Methyl-pyrazine-2-carboxylic acid [(1S,5R)-5-(3-methyl-benzoylamino)-bicyclo[3.2.1]oct-1-yl]-amide 135

6-Methyl-pyrazine-2-carboxylic acid {(1S,5R)-5-[(3-fluoro-pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1- yl}-amide 136

6-Methyl-pyrazine-2-carboxylic acid[(1R,5S)-5-(3,5-difluoro-benzoylamino)- bicyclo[3.2.1]oct-1-yl]-amide137

6-Methyl-pyrazine-2-carboxylic acid {(1R,5S)-5-[(6-methyl-pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1- yl}-amide 138

6-Methyl-pyrazine-2-carboxylic acid {(1R,5S)-5-[(4-methyl-thiazole-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1- yl}-amide 139

6-Methyl-pyrazine-2-carboxylic acid [(1R,5S)-5-(3-methyl-benzoylamino)-bicyclo[3.2.1]oct-1-yl]-amide 140

6-Methyl-pyrazine-2-carboxylic acid {(1R,5S)-5-[(3-fluoro-pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1- yl}-amide 141

Pyridine-2-carboxylic acid [(1S,5R)-5- (3-methyl-benzoylamino)-bicyclo[3.2.1]oct-1-yl]-amide 142

Pyridine-2-carboxylic acid [(1S,5R)-5- (3-fluoro-benzoylamino)-bicyclo[3.2.1]oct-1-yl]-amide 143

Pyridine-2-carboxylic acid {(1S,5R)-5-[(4-methyl-thiazole-2-carbonyl)-amino]- bicyclo[3.2.1]oct-1-yl}-amide144

2-Methyl-pyrimidine-4-carboxylic acid {(1R,5S)-5-[(pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide 145

5-Fluoro-pyridine-2-carboxylic acid {(1R,5S)-5-[(pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide 146

6-Fluoro-pyridine-2-carboxylic acid {(1R,5S)-5-[(pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide 147

3-Fluoro-6-methyl-pyridine-2-carboxylic acid{(1R,5S)-5-[(pyridine-2-carbonyl)- amino]-bicyclo[3.2.1]oct-1-yl}-amide148

Pyridine-2-carboxylic acid [(1S,5R)-5- (3-trifluoromethyl-benzoylamino)-bicyclo[3.2.1]oct-1-yl]-amide 149

Pyridine-2-carboxylic acid [(1S,5R)-5- (3-cyano-benzoylamino)-bicyclo[3.2.1]oct-1-yl]-amide 150

Pyridine-2-carboxylic acid [(1S,5R)-5- (3-cyano-5-fluoro-benzoylamino)-bicyclo[3.2.1]oct-1-yl]-amide 151

6-Methyl-pyrazine-2-carboxylic acid[(1S,5R)-5-(2,5-difluoro-benzoylamino)- bicyclo[3.2.1]oct-1-yl]-amide152

6-Methyl-pyrazine-2-carboxylic acid {(1S,5R)-5-[(6-fluoro-pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1- yl}-amide 153

6-Methyl-pyrazine-2-carboxylic acid [(1S,5R)-5-(3-cyano-5-fluoro-benzoylamino]-bicyclo[3.2.1]oct-1-yl]- amide 154

6-Methyl-pyrazine-2-carboxylic acid {(1S,5R)-5-[(5-fluoro-pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1- yl}-amide 155

6-Methyl-pyrazine-2-carboxylic acid{(1S,5R)-5-[(3,5-difluoro-pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1- yl}-amide 156

2-Methyl-pyrimidine-4-carboxylic acid {(1S,5R)-5-[(6-methyl-pyrazine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1- yl}-amide 157

2-Methyl-pyrimidine-4-carboxylic acid {(1R,5S)-5-[(6-methyl-pyrazine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1- yl}-amide 158

6-Methyl-pyrazine-2-carboxylic acid {(1R,5S)-5-[(pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide 159

6-Methyl-pyrazine-2-carboxylic acid {(1S,5R)-5-[(pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide 160

6-Methyl-pyrazine-2-carboxylic acid [(1R,5S)-5-(3-fluoro-benzoylamino)-bicyclo[3.2.1]oct-1-yl]-amide 161

6-Methyl-pyrazine-2-carboxylic acid [(1S,5R)-5-(3-fluoro-benzoylamino)-bicyclo[3.2.1]oct-1-yl]-amide 162

Pyrazine-2-carboxylic acid [(1S,5R)-5- (3-chloro-benzoylamino)-bicyclo[3.2.1]oct-1-yl]-amide 163

Pyrazine-2-carboxylic acid [(1R,5S)-5- (3-chloro-benzoylamino)-bicyclo[3.2.1]oct-1-yl]-amide

TABLE 2 Compounds of formula (I-B) Example No. Structure Chemical Name164

6-methyl-N-(5-(pyridin-2- ylcarbamoyl)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide 165

6-methyl-N-(5-(6-methylpyridin- 2- ylcarbamoyl)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide 166

6-methyl-N-(5-(2- methylpyrimidin-4- ylcarbamoyl)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide 167

6-methyl-N-(5-(4- methylthiazole-2- ylcarbamoyl)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide 168

6-methyl-N-(5-(thiazol-2- ylcarbamoyl)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide 169

6-methyl-N-(5-(6-methylpyridin- 2- ylcarbamoyl)bicyclo[3.2.1]octan-1-yl)picolinamide 170

2-methyl-N-(5-(6-methylpyridin- 2- ylcarbamoyl)bicyclo[3.2.1]octan-1-yl)pyrimidine-4-carboxamide 171

4-methyl-N-(5-(6-methylpyridin- 2- ylcarbamoyl)bicyclo[3.2.1]octan-1-yl)thiazole-2-carboxamide 172

N-(5-(6-methylpyridin-2- ylcarbamoyl)bicyclo[3.2.1]octan-1-yl)thiazole-2-carboxamide 173

5-methyl-N-(5-(6-methylpyridin- 2- ylcarbamoyl)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide 174

N-(5-(6-methylpyridin-2- ylcarbamoyl)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide 175

5-(3-methylbenzamido)-N-(6- methylpyridin-2- yl)bicyclo[3.2.1]octane-1-carboxamide 176

5-(3-chlorobenzamido)-N-(6- methylpyridin-2- yl)bicyclo[3.2.1]octane-1-carboxamide 177

N-(5-(6-methylpyridin-2- ylcarbamoyl)bicyclo[3.2.1]octan-1-yl)picolinamide 178

6-methyl-N-(5-(2- methylpyrimidin-4- ylcarbamoyl)bicyclo[3.2.1]octan-1-yl)picolinamide 179

2-methyl-N-(5-(2- methylpyrimidin-4- ylcarbamoyl)bicyclo[3.2.1]octan-1-yl)pyrimidine-4-carboxamide 180

4-methyl-N-(5-(2- methylpyrimidin-4- ylcarbamoyl)bicyclo[3.2.1]octan-1-yl)thiazole-2-carboxamide 181

5-(3-methylbenzamido)-N-(2- methylpyrimidin-4-yl)bicyclo[3.2.1]octane-1- carboxamide 182

5-(3-chlorobenzamido)-N-(2- methylpyrimidin-4-yl)bicyclo[3.2.1]octane-1- carboxamide 183

6-methyl-N-(5-(6-methylpyrazin- 2- ylcarbamoyl)bicyclo[3.2.1]octan-1-yl)picolinamide 184

4-methyl-N-(5-(6-methylpyrazin- 2- ylcarbamoyl)bicyclo[3.2.1]octan-1-yl)thiazole-2-carboxamide 185

5-(3-chlorobenzamido)-N-(6- methylpyrazin-2- yl)bicyclo[3.2.1]octane-1-carboxamide 186

5-(3-chlorobenzamido)-N- (pyridin-3- yl)bicyclo[3.2.1]octane-1-carboxamide 187

5-(3-chlorobenzamido)-N- (pyrazin-2- yl)bicyclo[3.2.1]octane-1-carboxamide

TABLE 3 Analytical data of compounds of formula I ESI-MS Example m/z No.¹H NMR (400 or 500 MHz, CDCl₃), δ (PPM) (M + H)⁺⁾ 1 8.23 (s, 2H),8.15-8.19 (m, 2H), 7.81-7.86 (m, 2H), 7.38-7.43 (m, 4H), 2.75- 351 2.80(m, 1H), 2.05-2.30 (m, 7H), 1.77-1.92 (m, 4H) 2 8.29 (s, 1H), 7.96 (d, J= 8.0 Hz, 2H), 7.69-7.74 (m, 2H), 7.57-7.61 (m, 1H), 398 7.44-7.48 (m,1H), 7.36 (t, J = 7.8 Hz, 2H), 7.24-7.28 (m, 1H), 6.17 (s, 1H),2.72-2.77 (m, 1H), 2.57 (s, 6H), 2.02-2.30 (m, 7H), 1.77-1.90 (m, 4H) 38.31 (s, 2H), 7.97 (d, J = 7.4 Hz, 2H), 7.71 (t, J = 7.7 Hz, 2H), 7.25(d, J = 379 7.9 Hz, 2H), 2.75-2.80 (m, 1H), 2.56 (s, 6H), 2.17-2.27 (m,5H), 2.09-2.15 (m, 2H), 1.77-1.91 (m, 4H) 4 9.17 (s, 1H), 8.57 (s, 1H),8.51-8.54 (m, 1H), 8.23 (s, 1H), 8.15-8.19 (m, 366 1H), 8.01 (s, 1H),7.82-7.87 (m, 1H), 7.39-7.44 (m, 1H), 2.77-2.82 (m, 1H), 2.60 (s, 3H),2.01-2.35 (m, 7H), 1.76-1.95 (m, 4H) 5 9.18 (s, 2H), 8.60 (s, 2H), 8.00(s, 2H), 2.77-2.83 (m, 1H), 2.60 (s, 6H), 2.16- 381 2.30 (m, 5H),2.06-2.12 (m, 2H), 1.77-1.93 (m, 4H) 6 9.17 (s, 1H), 8.60 (s, 1H), 7.99(s, 1H), 7.36-7.49 (m, 3H), 7.15-7.22 (m, 383 1H), 6.18 (s, 1H),2.73-2.78 (m, 1H), 2.60 (s, 3H), 2.01-2.30 (m, 7H), 1.75- 1.92 (m, 4H) 79.16 (s, 1H), 8.60 (s, 1H), 7.98 (s, 1H), 7.71-7.76 (m, 2H), 7.06-7.13(m, 383 2H), 6.18 (s, 1H), 2.73-2.78 (m, 1H), 2.60 (s, 3H), 2.11-2.29(m, 5H), 2.01- 2.09 (m, 2H), 1.75-1.92 (m, 4H) 8 9.18 (s, 1H), 8.85 (d,J = 5.1 Hz, 1H), 8.60 (s, 1H), 8.19 (s, 1H), 8.00 (s, 1H), 381 7.88 (d,J = 5.0 Hz, 1H), 2.77-2.83 (m, 1H), 2.77 (s, 3H), 2.60 (s, 3H), 2.05-2.29 (m, 7H), 1.75-1.92 (m, 4H) 9 8.67 (d, J = 5.0 Hz, 1H), 8.19 (s,1H), 7.72 (s, 1H), 7.61 (d, J = 7.0 Hz, 1H), 399 7.45 (d, J = 8.0 Hz,1H), 7.35 (t, J = 8.0 Hz, 1H), 7.26-7.25 (m, 1H), 6.26 (s, 1H), 2.72 (m,1H), 2.61 (s, 3H), 2.21-1.80 (m, 11H) 10 8.86 (d, J = 6.0 Hz, 2H), 8.16(s, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.62-7.60 (m, 385 1H), 7.44-7.41 (m,2H), 7.35-7.31 (m, 1H), 6.41 (s, 1H), 2.72 (m, 1H), 2.23- 1.79 (m, 11H)11 9.21 (s, 1H), 8.96 (d, J = 5.0 Hz, 1H), 8.13 (s, 1H), 8.08 (dd, J =5.0 Hz, 1.5 385 Hz, 1H), 7.70 (s, 1H), 7.59 (d, J = 7.5 Hz, 1H),7.47-7.45 (m, 1H), 7.36 (t, J = 8.0 Hz, 1H), 6.15 (s, 1H), 2.75 (d, J =12.5 Hz, 1H), 2.27-1.81 (m, 11H) 12 7.82 (s, 1H), 7.71 (s, 1H), 7.59(dd, J = 7.5 Hz, 1.5 Hz, 1H), 7.55 (d, J = 390 3.0 Hz, 1H), 7.44-7.32(m, 3H), 6.34 (s, 1H), 2.71 (m, 1H), 2.19-2.17 (m, 11H) 13 8.84 (d, J =6.0 Hz, 1H), 8.17 (s, 1H), 7.87 (d, J = 6.5 Hz, 1H), 7.70 (t, J = 3992.0 Hz, 1H), 7.60-7.58 (m, 1H), 7.45-7.27 (m, 2H), 6.27 (s, 1H),2.77-2.73 (m, 4H), 2.24-1.81 (m, 11H) 14 7.71 (d, J = 2.0 Hz, 1H), 7.60(d, J = 8.0 Hz, 1H), 7.44 (d, J = 9.0 Hz, 1H), 404 7.35-7.32 (m, 2H),7.09 (s, 1H), 6.38 (s, 1H), 2.70 (d, J = 10.5 Hz, 1H), 2.45 (s, 3H),2.24-1.78 (m, 11H) 15 7.92 (s, 1H), 7.69 (s, 1H), 7.58-7.33 (m, 3H),6.26 (s, 1H), 6.16 (s, 1H), 404 2.71-2.66 (m, 4H), 2.19-1.74 (m, 11H) 168.36 (d, J = 2.5 Hz, 1H), 8.35-8.17 (m, 1H), 8.03 (s, 1H), 7.70 (s, 1H),7.59 402 (d, J = 8.0 Hz, 1H), 7.54-7.50 (m, 1H), 7.44 (d, J = 8.0 Hz,1H), 7.36-7.33 (m, 1H), 6.28 (s, 1H), 2.73 (d, J = 10.0 Hz, 1H),2.26-1.75 (m, 11H) 17 8.33 (s, 1H), 8.14 (s, 1H), 8.04 (d J = 8.0 Hz,1H), 7.71 (t, J = 2.0 Hz, 1H), 398 7.63-7.58 (m, 2H), 7.45-7.43 (m, 1H),7.36-7.33 (m, 1H), 6.25 (s, 1H), 2.73 (d, J = 10.0 Hz, 1H), 2.39 (s,3H), 2.19-1.77 (m, 11H) 18 8.37 (d, J = 6.0 Hz, 1H), 8.20 (s, 1H), 7.96(s, 1H), 7.71 (d, J = 2.5 Hz, 1H), 398 7.60-7.58 (m, 1H), 7.47-7.20 (m,3H), 6.33 (s, 1H), 2.73-2.69 (m, 1H), 2.40 (s, 3H), 2.28-1.80 (m, 11H)19 8.71 (s, 1H), 8.49 (s, 1H), 7.84 (s, 1H), 7.60 (t, J = 2.0 Hz, 1H),7.58 (t, J = 398 2.0 Hz, 1H), 7.44-7.30 (m, 2H), 6.49 (s, 1H), 6.39 (s,1H), 2.70 (m, 1H), 2.35 (s, 3H), 2.21-1.80 (m, 11H) 20 9.38 (s, 1H),8.74 (d, J = 2.5 Hz, 1H), 8.50 (t, J = 2.0 Hz, 1H), 7.94 (s, 1H), 3697.47-7.37 (m, 3H), 7.20-7.18 (m, 1H), 6.17 (s, 1H), 2.76-2.73 (m, 1H),2.25- 2.13 (m, 5H), 2.06-2.01 (m, 2H), 1.89-1.81 (m, 4H) 21 8.53 (d, J =4.5 Hz, 1H), 8.21 (s, 1H), 8.16 (d, J = 8.0 Hz, 1H), 7.84 (t, J = 3688.0 Hz, 1H), 7.47-7.37 (m, 4H), 7.18 (t, J = 1.5 Hz, 1H), 6.19 (s, 1H),2.76- 2.74 (m, 1H), 2.30-1.80 (m, 11H) 22 8.75 (s, 2H), 7.61 (s, 2H),7.47-7.38 (m, 3H), 7.21-7.19 (m, 1H), 6.26 (s, 368 1H), 6.13 (s, 1H),2.75-2.73 (m, 1H), 2.25-1.83 (m, 11H) 23 8.34 (s, 1H), 8.16 (s, 1H),8.05 (d, J = 8.0 Hz, 1H), 7.63 (m, 1H), 7.49-7.45 382 (m, 2H), 7.41-7.38(m, 1H), 7.18 (m, 1H), 6.25 (s, 1H), 2.74 (m, 1H), 2.40 (s, 3H),2.34-2.25 (m, 1H), 2.21-1.78 (m, 10H) 24 8.36 (s, 1H), 7.98 (d, J = 8.0Hz, 1H), 7.72 (t, J = 7.5 Hz, 1 H), 7.48-7.39 (m, 382 3H), 7.28-7.26 (m,1H), 7.19 (t, J = 1.0 Hz, 1H), 6.19 (s, 1H), 2.76-2.74 (m, 1H), 2.58 (s,3H), 2.32-2.18 (m, 5H), 2.09-2.06 (m, 2H), 1.86-1.82 (m, 4H) 25 8.77 (d,J = 5.0 Hz, 1H), 8.10 (s, 1H), 7.80 (d, J = 5.0 Hz, 1H), 7.40-7.29 (m,383 3H), 7.12-7.09 (m, 1H), 6.15 (s, 1H), 2.70-2.66 (m, 4H), 2.17-1.72(m, 11H) 26 8.94 (s, 1H), 8.72 (d, J = 3.5 Hz, 1H), 8.08-8.06 (m, 1H),7.47-7.37 (m, 4H), 368 7.20-7.18 (m, 1H), 6.23 (s, 1H), 6.16 (s, 1H),2.74-2.71 (m, 1H), 2.24-2.13 (m, 5H), 2.05-2.00 (m, 2H), 1.87-1.79 (m,4H) 27 8.87 (d, J = 4.5 Hz, 2H), 8.18 (s, 1H), 7.50-7.38 (m, 4H),7.21-7.18 (m, 1H), 369 6.24 (s, 1H), 2.74-2.71 (m, 1H), 2.27-2.15 (m,5H), 2.09-2.04 (m, 2H), 1.92- 1.67 (m, 4H) 28 8.67 (d, J = 8.0 Hz, 1H),8.19 (s, 1H), 7.50-7.47 (m, 2H), 7.39-7.35 (m, 1H), 383 7.27-7.25 (m,1H), 7.18-7.14 (m, 1H), 6.38 (s, 1H), 2.71 (d, J = 10.0 Hz, 1H), 2.61(s, 3H), 2.25-1.79 (m, 11H) 29 7.47-7.37 (m, 2H), 7.41-7.36 (m, 1H),7.34 (s, 1H), 7.18 (t, J = 8.5 Hz, 1H), 388 7.09 (s, 1H), 6.18 (s, 1H),2.71 (d, J = 10.0 Hz, 1H), 2.40 (s, 3H), 2.25-1.80 (m, 11H) 30 7.91 (s,1H), 7.46-7.42 (m, 2H), 7.38 (d, J = 5.0 Hz, 1H), 7.17 (t, J = 8.0 Hz,388 1H), 6.19 (s, 1H), 6.06 (s, 1H), 2.71-2.67 (m, 4H), 2.20-1.79 (m,11H) 31 8.37 (d, J = 5.0 Hz, 1H), 8.20 (s, 1H), 7.97 (s, 1H), 7.47-7.44(m, 2H), 7.40- 382 7.36 (m, 1H), 7.22-7.17 (m, 2H), 6.23 (s, 1H),2.73-2.70 (m, 1H), 2.41 (s, 3H), 2.28-1.78 (m, 11H) 32 8.74 (s, 1H),8.54 (s, 1H), 7.89 (s, 1H), 7.47-7.39 (m, 3H), 7.18 (s, 1H), 6.25 382(s, 1H), 6.17 (s, 1H), 2.72 (m, 1H), 2.40 (s, 3H), 2.23-1.81 (m, 11H) 339.21 (s, 1H), 8.97 (d, J = 5.5 Hz, 1H), 8.14 (s, 1H), 8.09 (d, J = 5.0Hz, 1H), 369 7.47-7.37 (m, 3H), 7.20-7.17 (m, 1H), 6.16 (s, 1H), 2.75(d, J = 10.0 Hz, 1H), 2.27-1.79 (m, 11H) 34 7.83 (d, J = 3.5 Hz, 1H),7.55 (d, J = 3.0 Hz, 1H), 7.47-7.44 (m, 2H), 7.39- 374 7.38 (m, 2H),7.18 (s, 1H), 6.18 (s, 1H), 2.72 (d, J = 10.0 Hz, 1H), 2.26-1.78 (m,11H) 35 8.94 (s, 1H), 8.72 (s, 1H), 8.07 (d, J = 7.5 Hz, 1H), 7.54 (s,1H), 7.49 (d, J = 364 4.5 Hz, 1H), 7.38 (s, 1H), 7.30-7.26 (m, 2H), 6.29(s, 1H), 6.19 (s, 1H), 2.73- 2.71 (m, 1H), 2.39 (s, 3H), 2.26-1.67 (m,11H) 36 8.74 (d, J = 5.5 Hz, 2H), 7.60-7.49 (m, 4H), 7.31-7.30 (m, 2H),6.30 (s, 1H), 364 6.15 (s, 1H), 2.74-2.72 (m, 1H), 2.39 (s, 3H),2.28-1.78 (m, 11H) 37 9.16 (s, 1H), 8.59 (s, 1H), 8.00 (s, 1H), 7.54 (s,1H), 7.51-7.49 (m, 1H), 7.29- 379 7.27 (m, 2H), 6.27 (s, 1H), 2.75-2.73(m, 1H), 2.59 (s, 3H), 2.38 (s, 3H), 2.24-1.78 (m, 11H) 38 8.67 (d, J =6.5 Hz, 1H), 8.20 (s, 1H), 7.55 (s, 1H), 7.51-7.49 (m, 1H), 7.31- 3797.25 (m, 3H), 6.19 (s, 1H), 2.71-2.69 (m, 1H), 2.62 (s, 3H), 2.39 (s,3H), 2.23-1.80 (m, 11H) 39 8.73 (s, 1H), 8.56 (s, 1H), 7.88 (s, 1H),7.55 (s, 1H), 7.51 (d, J = 6.0 Hz, 1H), 378 7.32 (d, J = 6.0 Hz, 2H),6.20 (s, 1H), 6.18 (s, 1H), 2.71 (m, 1H), 2.41 (s, 6H), 2.26-1.84 (m,11H) 40 8.86 (d, J = 5.0 Hz, 2H), 8.18 (s, 1H), 7.55 (s, 1H), 7.51 (d, J= 6.0 Hz, 1H), 365 7.43 (m, 1H), 7.32-7.30 (m, 2H), 6.22 (s, 1H), 2.71(m, 1H), 2.41 (s, 3H), 2.27-1.83(m, 11H) 41 9.21 (s, 1H), 8.97 (d, J =5.0 Hz, 1H), 8.15 (s, 1H), 8.10 (d, J = 5.0 Hz, 1H), 365 7.54 (s, 1H),7.50 (d, J = 5.5 Hz, 1H), 7.32-7.26 (m, 2H), 6.17 (s, 1H), 2.74 (m, 1H),2.39 (s, 3H), 2.28-1.80 (m, 11H) 42 7.82 (s, 1H), 7.54-7.49 (m, 3H),7.41 (s, 1H), 7.30-7.27 (m, 2H), 6.31 (s, 370 1H), 2.70-2.68 (m, 1H),2.37 (s, 3H), 2.25-1.79 (m, 11H) 43 8.85 (d, J = 5.0 Hz, 1H), 8.19 (s,1H), 7.88 (d, J = 5.0 Hz, 1H), 7.54 (s, 1H), 379 7.50 (d, J = 6.0 Hz,1H), 7.32-7.26 (m, 2H), 6.19 (s, 1H), 2.77-2.73 (m, 4H), 2.39 (s, 3H),2.24-1.80 (m, 11H) 44 7.54 (s, 1H), 7.50-7.48 (m, 1H), 7.41 (s, 1H),7.32-7.26 (m, 2H), 7.10 (s, 384 1H), 6.17 (s, 1H), 2.71-2.69 (m, 1H),2.47 (s, 3H), 2.39 (s, 3H), 2.26-1.77 (m, 11H) 45 7.91 (s, 1H), 7.53 (s,1H), 7.49 (m, 1H), 7.30-7.26 (m, 2H), 6.14 (s, 1H), 384 5.96 (s, 1H),2.72-2.67 (m, 4H), 2.39 (s, 3H), 2.23-1.78 (m, 11H) 46 8.36 (d, J = 2.5Hz, 1H), 8.21-8.18 (m, 1H), 8.03 (s, 1H), 7.54-7.48 (m, 3H), 3827.30-7.26 (m, 2H), 6.18 (s, 1H), 2.73-2.70 (m, 1H), 2.39 (s, 3H),2.26-1.81 (m, 11H) 47 8.33 (s, 1H), 8.18 (s, 1H), 8.06 (d, J = 8.0 Hz,1H), 7.64 (d, J = 7.0 Hz, 1H), 378 7.54 (s, 1H), 7.50 (d, J = 6.0 Hz,1H), 7.30-7.26 (m, 2H), 6.20 (s, 1H), 2.72- 2.70 (m, 1H), 2.40 (s, 6H),2.30-1.79 (m, 11H) 48 8.37 (d, J = 5.0 Hz, 1H), 8.22 (s, 1H), 7.98 (s,1H), 7.54 (s, 1H), 7.50 (d, J = 378 6.5 Hz, 1H), 7.32-7.22 (m, 3H), 6.20(s, 1H), 2.72-2.70 (m, 1H), 2.42 (s, 3H), 2.39 (s, 3H), 2.27-1.80 (m,11H) 49 8.86 (d, J = 4.5 Hz, 1H), 8.37 (d, J = 3.0 Hz, 1H), 8.22-8.20(m, 2H), 8.05 384 (s, 1H), 7.89 (d, J = 4.5 Hz, 1H), 7.56-7.52 (m, 1H),2.80-2.78 (m, 4H), 2.28- 1.60 (m, 11H) 50 8.37 (d, J = 3.0 Hz, 1H), 8.31(s, 1H), 8.22-8.20 (m, 1H), 8.06 (s, 1H), 7.98 383 (d, J = 7.5 Hz, 1H),7.72 (t, J = 8.0 Hz, 1H), 7.55-7.51 (m, 1H), 7.27-7.26 (m, 1H),2.79-2.76 (m, 1H), 2.57 (s, 3H), 2.26-2.05 (m, 7H), 1.88-1.84 (m, 4H) 519.17 (s, 1H), 8.59 (s, 1H), 8.36 (d, J = 3.0 Hz, 1H), 8.21-8.18 (m, 1H),8.04 384 (s, 1H), 8.00 (s, 1H), 7.54-7.50 (m, 1H), 2.79-2.76 (m, 1H),2.59 (s, 3H), 2.28-1.80 (m, 11H) 52 9.25 (s, 1H), 9.18 (s, 1H), 8.61 (s,1H), 8.36 (s, 1H), 8.01 (s, 1H), 7.91 (s, 381 1H), 2.80 (m, 1H), 2.66(s, 3H), 2.58 (s, 3H), 2.27-1.84 (m, 11H) 53 9.25 (s, 1H), 8.36(s, 1H),7.90 (s, 1H), 7.55-7.50 (m, 2H), 7.32-7.30 (m, 379 2H), 6.19 (s, 1H),2.74 (d, J = 9.5 Hz, 1H), 2.66 (s, 3H), 2.40 (s, 3H), 2.28- 1.83 (m,11H) 54 9.25 (s, 1H), 8.36 (s, 1H), 7.90 (s, 1H), 7.48-7.40 (m, 3H),7.27-7.19 (m, 383 1H), 6.17 (s, 1H), 2.75 (m, 1H), 2.66 (s, 3H),2.28-1.83 (m, 11H) 55 9.25 (s, 1H), 8.96 (s, 1H), 7.90 (s, 1H), 7.71 (s,1H), 7.66-7.36 (m, 3H), 6.17 399 (s, 1H), 2.76-2.74 (m, 1H), 2.66 (s,3H), 2.25-1.82 (m, 11H) 56 9.25-9.22 (m, 2H), 8.98 (d, J = 5.0 Hz, 1H),8.36 (s, 1H), 8.11-8.09 (m, 2H), 367 7.90 (s, 1H), 2.79 (d, J = 10.0 Hz,1H), 2.66 (s, 3H), 2.28-1.86 (m, 11H) 57 9.25 (s, 1H), 8.36 (d, J = 4.5Hz, 1H), 7.90-7.84 (m, 2H), 7.56 (d, J = 3.0 Hz, 372 1H), 7.40 (s, 1H),2.76 (d, J = 10.0 Hz, 1H), 2.65 (s, 3H), 2.27-1.81 (m, 11H) 58 9.25 (s,1H), 8.36 (s, 1H), 7.91 (s, 1H), 7.74-7.72 (m, 2H), 7.50-7.42 (m, 3H),365 6.22 (s, 1H), 2.75 (m, 1H), 2.65 (s, 3H), 2.26-1.82 (m, 11H) 59 9.25(s, 1H), 8.69 (d, J = 5.0 Hz, 1H); 8.36 (s, 2H), 7.90 (s, 1H), 7.27 (s,381 1H), 2.76-2.74 (m, 1H), 2.65 (s, 3H), 2.63 (s, 3H), 2.27-1.82 (m,11H) 60 9.25 (s, 1H), 8.86 (d, J = 5.0 Hz, 1H), 8.36 (s, 1H), 8.20 (s,1H), 7.91-7.88 381 (m, 2H), 2.80-2.78 (m, 4H), 2.66 (s, 3H), 2.28-1.85(m, 11H) 61 9.24 (s, 1H), 8.35 (s, 1H), 7.90 (s, 1H), 7.37 (s, 1H), 7.10(s, 1H), 2.75 (m, 386 1H), 2.65 (s, 3H), 2.47 (s, 3H), 2.26-1.82 (m,11H) 62 9.25 (s, 1H), 8.37-8.19 (m, 3H), 8.05 (s, 1H), 7.91 (s, 1H),7.55-7.51 (m, 384 1H), 2.77 (m, 1H), 2.65 (s, 3H), 2.27-1.84 (m, 11H) 639.25 (s, 1H), 8.35-8.34 (m, 2H), 8.17 (s, 1H), 8.05 (d, J = 10.5 Hz,1H), 7.91 380 (s, 1H), 7.64-7.62 (m, 1H), 2.77 (m, 1H), 2.65 (s, 3H),2.40 (s, 3H), 2.29- 1.83 (m, 11H) 64 9.25 (s, 1H), 8.38-8.35 (m, 2H),8.22 (s, 1H), 7.99 (s, 1H), 7.91 (s, 1H), 7.23- 380 7.22 (m, 1H), 2.76(m, 1H), 2.65 (s, 3H), 2.43 (s, 3H), 2.29-1.81 (m, 11H) 65 398 66 9.17(s, 1H), 8.59 (s, 1H), 8.06-8.00 (m, 2H), 7.47-7.43 (m, 1H), 7.26-7.24383 (m, 1H), 7.12-7.08 (m, 1H), 6.87-6.85 (m, 1H), 2.74-2.72 (m, 1H),2.60 (s, 3H), 2.24-1.79 (m, 11H) 67 9.17 (s, 1H), 8.60 (s, 1H), 7.98 (s,1H), 7.26-7.23 (m, 2H), 6.93 (t, J = 3.5 401 Hz, 1H), 6.12 (s, 1H),2.76-2.74 (m, 1H), 2.60 (s, 3H), 2.26-2.14 (m, 5H), 2.07-2.01 (m, 2H),1.87-1.80 (m, 4H) 68 9.10 (s, 1H), 8.86 (s, 1H), 8.65 (d, J = 3.5 Hz,1H), 8.53 (s, 1H), 8.01-7.99 366 (m, 1H), 7.92 (s, 1H), 7.32-7.30 (m,1H), 6.16 (s, 1H), 2.72-2.71 (m, 1H), 2.53 (s, 3H), 2.20-1.74 (m, 11H)69 9.09 (s, 1H), 8.52 (s, 1H), 7.91 (s, 1H), 7.63 (s, 1H), 7.52 (d, J =8.0 Hz, 399 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.29 (t, J = 8.0 Hz, 1H),6.12 (s, 1H), 2.69-2.67 (m, 1H), 2.53 (s, 3H), 2.21-1.75 (m, 11H) 709.19 (s, 1H), 8.69 (d, J = 5.5 Hz, 1H), 8.61 (s, 1H), 8.22 (s, 1H), 8.01(s, 381 1H), 7.27 (s, 1H), 2.78 (m, 1H), 2.63 (s, 3H), 2.61 (s, 3H),2.28-1.62 (m, 11H) 71 9.23 (s, 1H), 9.19 (s, 1H), 8.98 (d, J = 5.0 Hz,1H), 8.61 (s, 1H), 8.16 (s, 367 1H), 8.11 (m, 1H), 8.01 (s, 1H), 2.82(m, 1H), 2.61 (s, 3H), 2.29-1.86 (m, 11H) 72 9.19 (s, 1H), 8.61 (s, 1H),8.00 (s, 1H), 7.85 (d, J = 3.0 Hz, 1H), 7.57 (d, J = 372 3.0 Hz, 1H),7.41(s, 1H), 2.79 (m, 1H), 2.61 (s, 3H), 2.27-1.83 (m, 11H) 73 9.17 (s,1H), 8.60 (s, 1H), 7.99 (s, 1H), 7.73 (d, J = 8.0 Hz, 2H), 7.50-7.41 365(m, 3H), 7.18 (s, 1H), 2.77 (m, 1H), 2.60 (s, 3H), 2.25-1.83 (m, 11H) 749.19 (s, 1H), 8.61 (s, 1H), 8.03 (s, 1H), 7.36 (s, 1H), 7.11 (s, 1H),2.79 (m, 386 1H), 2.61 (s, 3H), 2.48 (s, 3H), 2.26-1.82 (m, 11H) 75 9.17(s, 1H), 8.59 (s, 1H), 8.33 (s, 1H), 8.16 (s, 1H), 8.06 (d, J = 8.0 Hz,1H), 380 8.00 (s, 1H), 7.63 (d, J = 7.5 Hz, 1H), 2.79 (m, 1H), 2.59 (s,3H), 2.40 (s, 3H), 2.30-1.83 (m, 11H) 76 9.18 (s, 1H), 8.60 (s, 1H),8.39 (d, J = 5.0 Hz, 1H), 8.23 (s, 1H), 8.02 (d, J = 380 10.0 Hz, 2H),7.24 (d, J = 5.0 Hz, 1H), 2.80 (m, 1H), 2.61 (s, 3H), 2.43 (s, 3H),2.25-1.83 (m, 11H) 77 9.17 (s, 1H), 8.72 (s, 1H), 8.60 (s, 1H), 8.54 (s,1H), 7.98 (s, 1H), 7.87 (s, 380 1H), 6.18 (s, 1H), 2.77 (d, J = 10.0 Hz,1H), 2.60 (s, 3H), 2.39 (s, 3H), 2.27- 1.84 (m, 11H) 78 9.40 (s, 1H),9.19 (s, 1H), 8.76 (d, J = 3.0 Hz, 1H), 8.61 (s, 1H), 8.52 (t, J = 3672.0 Hz, 1H), 8.01 (s, 1H), 7.96 (s, 1H), 2.82 (d, J = 10.0 Hz, 1H), 2.61(s, 3H), 2.29-1.86 (m, 11H) 79 9.18 (s, 1H), 8.88 (d, J = 2.0 Hz, 2H),8.61 (s, 1H), 8.20 (t, J = 2.0 Hz, 1H), 367 8.01 (s, 1H), 7.44 (s, 1H),2.79 (d, J = 10.0 Hz, 1H), 2.62 (s, 3H), 2.29-1.82 (m, 11H) 80 9.19 (s,1H), 8.61 (s, 1H), 8.35 (s, 1H), 8.03-7.98 (m, 2H), 7.75-7.72 (t, J =380 8.0 Hz, 1H), 7.29 (s, 1H), 2.81-2.79 (m, 1H), 2.61 (s, 3H), 2.59 (s,3H), 2.25- 1.85 (m, 11H) 81 8.74 (s, 1H), 8.55 (s, 1H), 8.30 (s, 1H),8.24 (s, 1H), 7.98 (d, J = 8.0 Hz, 1H), 379 7.90 (s, 1H), 7.73 (t, J =8.0 Hz, 1H), 7.27 (s, 1H), 6.24 (s, 1H), 2.77-2.75 (m 1H), 2.57 (s, 3H),2.40 (s, 3H), 2.26-1.82 (m, 11H) 82 8.30 (s, 1H), 7.98 (d, J = 7.5 Hz,1H), 7.73 (t, J = 8.0 Hz, 1H), 7.56-7.50 (m, 378 2H), 7.32-7.27 (m, 3H),6.21 (s, 1H), 2.74 (m, 1H), 2.57 (s, 3H), 2.51 (s, 3H), 2.21-1.81 (m,11H) 83 9.40 (s, 1H), 8.75 (d, J = 3.0 Hz, 1H), 8.52 (d, J = 4.0 Hz,1H), 8.31 (s, 1H), 366 7.98-7.97 (m, 1H), 7.73 (t, J = 8.0 Hz, 1H), 7.27(s, 1H), 2.79 (m, 1H), 2.57 (s, 3H), 2.28-1.82 (m, 11H) 84 8.87-8.86 (m,2H), 8.32 (s, 1H), 8.20 (s, 1H), 7.98 (d, J = 7.0 Hz, 1H), 7.73 366 (t,J = 8.0 Hz, 1H), 7.43 (t, J = 5.0 Hz, 1H), 7.28 (s, 1H), 2.78-2.76 (m,1H), 2.58 (s, 3H), 2.28-1.82 (m, 11H) 85 9.23 (d, J = 2.0 Hz, 1H), 8.98(d, J = 5.0 Hz, 1H), 8.31 (s, 1H), 8.17-8.10 366 (m, 2H), 7.98 (d, J =8.0 Hz, 1H), 7.73 (t, J = 8.0 Hz, 1H), 7.28 (s, 1H), 2.79 (m, 1H), 2.57(s, 3H), 2.28-1.82 (m, 11H) 86 8.30 (s 1H), 7.97 (d, J = 8.0 Hz, 1H),7.85 (d, J = 3.5 Hz, 1H), 7.72 (t, J = 371 7.5 Hz, 1H), 7.56 (d, J = 3.0Hz, 1H), 7.41 (s, 1H), 7.27 (s, 1H), 2.76 (m, 1H), 2.57 (s, 3H),2.28-1.82 (m, 11H) 87 8.31 (s 1H), 7.98 (d, J = 7.5 Hz, 1H), 7.74-7.71(m, 3H), 7.50-7.42 (m, 3H), 364 7.27 (s, 1H), 6.22 (s, 1H), 2.75 (m,1H), 2.57 (s, 3H), 2.28-1.82 (m, 11H) 88 9.26 (d, J = 1.0 Hz, 1H),8.36-8.32 (m, 2H), 7.99-7.92 (m, 2H), 7.73 (t, J = 380 8.0 Hz, 1H), 7.27(s, 1H), 2.78 (m, 1H), 2.66 (s, 3H), 2.57 (s, 3H), 2.27-1.84 (m, 11H) 898.68 (d, J = 5.0 Hz, 1H), 8.30 (s, 1H), 8.22 (s, 1H), 7.98 (d, J = 7.5Hz, 1H), 380 7.71 (t, J = 8.0 Hz, 1H), 7.27-7.25 (m, 2H), 2.77 (m, 1H),2.62 (s, 3H), 2.57 (s, 3H), 2.27-1.82 (m, 11H) 90 8.86 (d, J = 5.0 Hz,1H), 8.31 (s, 1H), 8.21 (s, 1H), 7.98 (d, J = 8.0 Hz, 1H), 380 7.90 (d,J = 5.5 Hz, 1H), 7.73 (t, J = 8.0 Hz, 1H), 7.28 (s, 1H), 2.81-2.78 (m,4H), 2.57 (s, 3H), 2.30-1.84 (m, 11H) 91 8.28 (s, 1H), 7.97 (d, J = 7.5Hz, 1H), 7.92 (s, 1H), 7.73 (t, J = 8.0 Hz, 1H), 385 7.27 (s, 1H), 5.99(s, 1H), 2.74-2.72 (m, 4H), 2.57 (s, 3H), 2.26-1.82 (m, 11H) 92 8.34 (m,2H), 8.20 (s, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H),379 7.73 (t, J = 8.0 Hz, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.27 (s, 1H),2.77 (m, 1H), 2.57 (s, 3H), 2.41 (s, 3H), 2.26-1.82 (m, 11H) 93 8.38 (d,J = 5.5 Hz, 1H), 8.32 (s, 1H), 8.24 (s, 1H), 8.00-7.97 (m, 2H), 7.72 379(t, J = 8.0 Hz, 1H), 7.27-7.22 (m, 2H), 2.78-2.76 (m, 1H), 2.57 (s, 3H),2.43 (s, 3H), 2.26-1.82 (m, 11H) 94 384 95 9.38 (s, 1H), 8.75 (s, 1H),8.51 (m, 1H), 7.99 (s, 1H), 7.89-7.97 (m, 2H), 7.74 419 (m, 1H), 7.58(m, 1H), 6.21 (s, 1H), 2.79 (m, 1H), 1.78-2.35 (m, 11H) 96 9.38 (s, 1H),8.75 (m, 1H), 8.51 (m, 1H), 8.02 (s, 1H), 7.89-7.99 (m, 2H), 376 7.78(m, 1H), 7.57 (m, 1H), 6.20 (s, 1H), 2.78 (m, 1H), 1.78-2.32 (m, 11H) 979.40 (s, 1H), 8.73 (m, 1H), 8.50 (m, 1H), 8.07 (m, 1H), 7.90-7.99 (m,2H), 370 7.85 (m, 1H), 7.07 (m, 1H), 2.78 (m, 1H), 1.78-2.32 (m, 11H) 989.38 (d, J = 2.5 Hz, 1H), 8.74 (d, J = 2.5 Hz, 1H), 8.51-8.50 (m, 1H),7.95 365 (s, 1H), 7.54 (s, 1H), 7.50-7.49 (d, J = 6.0 Hz, 1H), 7.31-7.30(d, J = 5.5 Hz, 2H), 6.18 (s, 1H), 2.75-2.73 (m, 1H), 2.39 (s, 3H),2.25-1.82 (m, 11H) 99 9.39 (d, J = 2.0 Hz, 1H), 8.75 (d, J = 2.5 Hz,1H), 8.52-8.51 (t, J = 2.0 Hz, 385 1H), 7.95 (s, 1H), 7.72 (t, J = 2.0Hz, 1H), 7.61-7.60 (d, J = 7.0 Hz, 1H), 7.48- 7.46 (m, 1H), 7.39-7.36(m, 1H), 6.18 (s, 1H), 2.77-2.75 (m, 1H), 2.27-1.82 (m, 11H) 100 9.39(d, J = 1.0 Hz, 1H), 8.85 (d, J = 5.0 Hz, 1H), 8.75 (d, J = 2.0 Hz, 1H),367 8.50 (s, 1H), 8.19 (s, 1H), 7.95 (s, 1H), 7.88 (d, J = 5.0 Hz, 1H),2.81 (m, 1H), 2.77 (s, 3H), 2.28-1.84 (m, 11H) 101 9.39 (d, J = 1.0 Hz,1H), 8.75 (d, J = 2.0 Hz, 1H), 8.52 (t, J = 2.0 Hz, 1H), 372 7.96 (s,1H), 7.37 (s, 1H), 7.11 (s, 1H), 2.78 (m, 1H), 2.47 (s, 3H), 2.27-1.84(m, 11H) 102 9.38 (d, J = 1.0 Hz, 1H), 8.74 (d, J = 2.5 Hz, 1H), 8.50(d, J = 2.0 Hz, 1H), 370 8.36 (d, J = 2.0 Hz, 1H), 8.21 (m, 1H), 8.04(s, 1H), 7.95 (s, 1H), 7.54-7.51 (m, 1H), 2.79 (m, 1H), 2.27-1.84 (m,11H) 103 9.40 (d, J = 1.5 Hz, 1H), 8.75 (d, J = 2.5 Hz, 1H), 8.52 (t, J= 2.0 Hz, 1H), 366 8.39 ((d, J = 4.5 Hz, 1H), 8.23 (s, 1H), 8.00 (s,1H), 7.97 (s, 1H), 7.24 (d, J = 5.0 Hz, 1H), 2.77-2.75 (m, 1H), 2.43 (s,3H), 2.22-1.84 (m, 11H) 104 8.85 (d, J = 5.0 Hz, 1H), 8.54-8.53 (m, 1H),8.23-8.17 (m, 3H), 7.89-7.84 (m, 366 2H), 7.44-7.41 (m, 1H), 2.80-2.78(m, 4H), 2.23-1.82 (m, 11H) 105 8.54 (d, J = 5.0 Hz, 1H), 8.32 (s, 1H),8.25 (s, 1H), 8.18 (d, J = 8.0 Hz, 1H), 365 7.98 (d, J = 7.5 Hz, 1H),7.87-7.83 (m, 1H), 7.73-7.70 (m, 1H), 7.43-7.41 (m, 1H), 7.27-7.26 (m,1H), 2.79-2.77 (m, 1H), 2.57 (s, 3H), 2.27-1.82 (m, 11H) 106 9.25 (s,1H), 8.84 (d, J = 4.0 Hz, 1H), 8.36 (s, 1H), 8.24 (s, 1H), 8.18 (d, J =366 6.0 Hz, 1H), 7.92-7.84 (m, 2H), 7.43 (dd, J = 12.0 Hz, 5.0 Hz, 1H),2.79-2.77 (m, 1H), 2.65 (s, 3H), 2.25-1.57 (m, 11H) 107 8.69 (d, J = 5.0Hz, 1H), 8.54 (d, J = 5.0 Hz, 1H), 8.23-8.17 (m, 3H), 7.86- 366 7.83 (m,1H), 7.43-7.41 (m, 1H), 7.27-7.25 (m, 1H), 2.77-2.74 (m, 1H), 2.63 (s,3H), 2.26-1.82 (m, 11H) 108 8.54 (d, J = 5.0 Hz, 1H), 8.22-8.17 (m, 2H),7.85 (m, 1H), 7.43-7.39 (m, 2H), 371 7.10 (s, 1H), 2.77-2.75 (m, 1H),2.47 (s, 3H), 2.27-1.84 (m, 11H) 109 8.53 (d, J = 4.5 Hz, 1H), 8.21-8.16(m, 2H), 7.92 (s, 1H), 7.86-7.83 (m, 1H), 371 7.43-7.41 (m, 1H), 6.04(s, 1H), 2.74-2.72 (m, 4H), 2.29-1.78 (m, 11H) 110 8.54 (d, J = 4.0 Hz,1H), 8.37 (d, J = 3.0 Hz, 1H), 8.27-8.18 (m, 3H), 8.06 369 (s, 1H), 7.86(t, J = 8.0 Hz, 1H), 7.53-7.42 (m, 2H), 2.78-2.76 (m, 1H), 2.27- 1.84(m, 11H) 111 8.52 (d, J = 4.5 Hz, 1H), 8.33 (s, 1H), 8.23 (s, 1H), 8.19(s, 1H), 8.17 (d, J = 365 7.5 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H),7.85-7.82 (m, 1H), 7.64 (dd, J = 8.0 Hz, 1.5 Hz, 1H), 7.42-7.39 (m, 1H),2.77-2.75 (m, 1H), 2.39 (s, 3H), 2.27-1.80 (m, 11H) 112 8.54 (d, J = 5.0Hz, 1H), 8.38 (d, J = 5.0 Hz, 1H), 8.25 (m, 2H), 8.18 (d, J = 365 8.0Hz, 1H), 8.00 (s, 1H), 7.85 (t, J = 8.0 Hz, 1H), 7.42-7.39 (m, 1H), 7.22(d, J = 5.0 Hz, 1H), 2.77-2.75 (m, 1H), 2.43 (s, 3H), 2.27-1.84 (m, 11H)113 8.73 (s, 1H), 8.54 (d, J = 5.0 Hz, 2H), 8.23-8.16 (m, 2H), 7.89-7.84(m, 2H), 365 7.44-7.42 (m, 1H), 6.24 (s, 1H), 2.77-2.75 (m, 1H), 2.40(s, 3H), 2.32-1.81 (m, 11H) 114 8.54 (d, J = 4.0 Hz, 1H), 8.23 (s, 1H),8.18 (d, J = 8.0 Hz, 1H), 7.85 (t, J = 364 7.5 Hz, 1H), 7.55 (s, 1H),7.51 (d, J = 6.5 Hz, 1H), 7.44-7.27 (m, 3H), 6.22 (s, 1H), 2.75-2.73 (m,1H), 2.42 (s, 3H), 2.40-1.80 (m, 11H) 115 8.54 (d, J = 5.0 Hz, 1H), 8.22(s, 1H), 8.18 (d, J = 7.5 Hz, 1H), 7.85 (t, J = 384 8.0 Hz, 1H), 7.72(s, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.47-7.27 (m, 3H), 6.20 (s, 1H),2.76-2.73 (m, 1H), 2.30-1.80 (m, 11H) 116 8.35 (s, 1H), 8.10 (s, 1H),8.00 (d, J = 8.0 Hz, 1H), 7.75 (t, J = 7.5 Hz, 1H), 397 7.24-7.43 (m,3H), 2.80 (m, 1H), 2.60 (s, 3H), 2.57 (s, 3H), 1.78-2.30 (m, 11H) 1178.28 (s, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.72 (t, J = 7.5 Hz, 1H),7.36-7.50 (m, 382 3H), 7.25-7.29 (m, 1H), 7.19 (t, J = 1.0 Hz, 1H), 6.20(s, 1H), 2.74-2.76 (m, 1H), 2.58 (s, 3H), 1.78-2.32 (m, 11H) 118 8.30(s, 1H), 7.98 (d, J = 7.5 Hz, 1H), 7.73 (t, J = 8.0 Hz, 1H), 7.48-7.60(m, 378 2H), 7.22-7.32 (m, 3H), 6.20 (s, 1H), 2.72-2.78 (m, 1H), 2.58(s, 3H), 2.41 (s, 3H), 1.78-2.32 (m, 11H) 119 8.54 (d, J = 5.0 Hz, 1H),8.32 (s, 1H), 8.25 (s, 1H), 8.18 (d, J = 8.0 Hz, 1H), 365 7.98 (d, J =7.5 Hz, 1H), 7.87-7.83 (m, 1H), 7.73-7.70 (m, 1H), 7.43-7.41 (m, 1H),7.27-7.26 (m, 1H), 2.79-2.77 (m, 1H), 2.57 (s, 3H), 1.78-2.32 (m, 11H)120 8.86 (d, J = 5.0 Hz, 1H), 8.31 (s, 1H), 8.21 (s, 1H), 7.98 (d, J =8.0 Hz, 1H), 380 7.90 (d, J = 5.5 Hz, 1H), 7.73 (t, J = 8.0 Hz, 1H),7.22-7.30 (m, 1H), 2.75- 2.83 (m, 4H), 2.58 (s, 3H), 1.78-2.32 (m, 11H)121 9.22 (d, J = 2.0 Hz, 1H), 8.98 (d, J = 5.0 Hz, 1H), 8.31 (s, 1H),8.18 (s, 1H), 366 8.09-8.12 (m, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.72 (t,J = 8.0 Hz, 1H), 7.22- 7.30 (m, 1H), 2.75-2.82 (m, 1H), 2.57 (s, 3H),1.78-2.32 (m, 11H) 122 8.40 (s, 1H), 8.00 (d, J = 7.5 Hz, 1H), 7.74-7.79(m, 3H), 7.41-7.54 (m, 3H), 364 7.27 (s, 1H), 6.24 (s, 1H), 2.75 (m,1H), 2.60 (s, 3H), 1.76-2.32 (m, 1H) 123 8.35 (s, 1H), 8.10 (s, 1H),8.00 (d, J = 8.0 Hz, 1H), 7.75 (t, J = 7.5 Hz, 1H), 397 7.24-7.43 (m,3H), 2.80 (m, 1H), 2.60 (s, 3H), 2.57 (s, 3H), 1.78-2.30 (m, 11H) 1248.86 (d, J = 5.0 Hz, 1H), 8.31 (s, 1H), 8.21 (s, 1H), 7.98 (d, J = 8.0Hz, 1H), 380 7.90 (d, J = 5.5 Hz, 1H), 7.73 (t, J = 8.0 Hz, 1H),7.22-7.30 (m, 1H), 2.75- 2.83 (m, 4H), 2.58 (s, 3H), 1.78-2.32 (m, 11H)125 8.28 (s, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.72 (t, J = 7.5 Hz, 1H),7.36-7.50 (m, 382 3H), 7.25-7.29 (m, 1H), 7.19 (t, J = 1.0 Hz, 1H), 6.18(s, 1H), 2.72-2.78 (m, 1H), 2.56 (s, 3H), 1.78-2.32 (m, 11H) 126 8.54(d, J = 5.0 Hz, 1H), 8.32 (s, 1H), 8.25 (s, 1H ), 8.18 (d, J = 8.0 Hz,1H), 365 7.98 (d, J = 7.5 Hz, 1H), 7.87-7.83 (m, 1H), 7.73-7.70 (m, 1H),7.43-7.41 (m, 1H), 7.27-7.26 (m, 1H), 2.77-2.79 (m, 1H), 2.57 (s, 3H),1.78-2.32 (m, 11H) 127 9.22 (d, J = 2.0 Hz, 1H), 8.98 (d, J = 5.0 Hz,1H), 8.31 (s, 1H), 8.18 (s, 1H), 366 8.09-8.12 (m, 1H), 7.97 (d, J = 8.0Hz, 1H), 7.72 (t, J = 8.0 Hz, 1H), 7.22- 7.30 (m, 1H), 2.75-2.82 (m,1H), 2.57 (s, 3H), 1.78-2.32 (m, 11H) 128 8.37 (d, J = 3.0 Hz, 1H), 8.31(s, 1H), 8.17-8.22 (m, 1H), 8.05 (s, 1H), 7.98 383 (d, J = 7.5 Hz, 1H),7.72 (t, J = 8.0 Hz, 1H), 7.48-7.55 (m, 1H), 7.25-7.30 (m, 1H),2.73-2.80 (m, 1H), 2.57 (s, 3H), 1.78-2.30 (m, 11H) 129 8.35 (s, 1H),8.00 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 3.5 Hz, 1H), 7.74 (t, J = 371 7.5Hz, 1H), 7.56 (d, J = 3.0 Hz, 1H), 7.45 (s, 1H), 7.24-7.32 (m, 1H), 2.78(m, 1H), 2.60 (s, 3H), 1.78-2.32 (m, 11H) 130 8.40 (d, J = 5.5 Hz, 1H),8.35 (s, 1H), 8.29 (s, 1H), 7.89-8.02 (m, 2H), 7.72 379 (t, J = 8.0 Hz,1H), 7.15-7.33 (m, 2H), 2.76 (m, 1H), 2.58 (s, 3H), 2.42 (s, 3H),1.75-2.28 (m, 11H) 131 8.32 (s, 1H), 8.20 (m, 1H), 8.12 (m, 1H), 8.05(s, 1H), 7.97 (m, 1H), 7.70 (t, J = 395 8.0 Hz), 7.23-7.29 (m, 2H), 3.91(s, 3H), 2.78 (m, 1H), 2.57 (s, 3H), 1.78- 2.30 (m, 11H) 132 9.19 (s,1H), 8.61 (s, 1H), 8.35 (s, 1H), 7.98-8.03 (m, 2H), 7.72-7.75 (t, J =380 8.0 Hz, 1H), 7.29 (s, 1H), 2.82 (m, 1H), 2.61 (s, 3H), 2.59 (s, 3H),1.82-2.32 (m, 11H) 133 9.19 (s, 1H), 8.61 (s, 1H), 8.03 (s, 1H), 7.36(s, 1H), 7.11 (s, 1H), 2.79 (m, 386 1H), 2.61 (s, 3H), 2.48 (s, 3H),1.80-2.32 (m, 11H) 134 9.17 (s, 1H), 8.60 (s, 1H), 7.99 (s, 1H), 7.57(s, 1H), 7.50-7.60 (m, 1H), 7.28- 379 7.40 (m, 2H), 6.20 (s, 1H), 2.78(m, 1H), 2.61 (s, 3H), 2.40 (s, 3H), 1.78-2.32 (m, 11H) 135 9.19 (s,1H), 8.61 (s, 1H), 7.82-8.09 (m, 4H), 7.06-7.12 (m, 1H), 2.80 (m, 3841H), 2.61 (s, 3H), 1.78-2.32 (m, 11H) 136 9.16(s, 1H), 8.60 (s, 1H),7.99 (s, 1H), 7.20-7.30 (m, 2H), 6.89-6.97 (m, 1H), 401 6.27 (s, 1H),2.75 (m, 1H), 2.60 (s, 3H), 1.78-2.31 (m, 11H) 137 9.19 (s, 1H), 8.61(s, 1H), 8.35 (s, 1H), 7.98-8.03 (m, 2H), 7.72-7.75 (t, J = 380 8.0 Hz,1H), 7.29 (s, 1H), 2.82 (m, 1H), 2.61 (s, 3H), 2.59 (s, 3H), 1.82-2.32(m, 11H) 138 9.19 (s, 1H), 8.61 (s, 1H), 8.03 (s, 1H), 7.36 (s, 1H),7.11 (s, 1H), 2.79 (m, 386 1H), 2.61 (s, 3H), 2.48 (s, 3H), 1.80-2.32(m, 11H) 139 9.17 (s, 1H), 8.60 (s, 1H), 7.99 (s, 1H), 7.57 (s, 1H),7.50-7.60 (m, 1H), 7.28- 379 7.40 (m, 2H), 6.20 (s, 1H), 2.78 (m, 1H),2.61 (s, 3H), 2.40 (s, 3H), 1.78-2.32 (m, 11H) 140 9.19 (s, 1H), 8.61(s, 1H), 7.82-8.09 (m, 4H), 7.06-7.12 (m, 1H), 2.80 (m, 384 1H), 2.61(s, 3H), 1.78-2.32 (m, 11H) 141 8.54 (d, J = 4.0 Hz, 1H), 8.23 (s, 1H),8.18 (d, J = 8.0 Hz, 1H), 7.88 (t, J = 7.5 364 Hz, 1H), 7.55 (s, 1H),7.53 (d, J = 6.5 Hz, 1H), 7.27-7.50 (m, 3H), 6.20 (s, 1H), 2.75 (m, 1H),2.44 (s, 3H), 1.78-2.32 (m, 11H) 142 8.54 (d, J = 5.0 Hz, 1H), 8.30 (s,1H), 8.20 (d, J = 7.5 Hz, 1H), 7.88 (t, J = 368 8.0 Hz, 1H), 7.36-7.50(m, 4H), 7.16-7.22 (m, 1H), 6.20 (s, 1H), 2.75 (m, 1H), 1.78-2.32 (m,11H) 143 8.54 (d, J = 5.0 Hz, 1H), 8.30 (s, 1H), 8.20 (d, J = 7.5 Hz,1H), 7.88 (t, J = 371 8.0 Hz, 1H), 7.35-7.48 (m, 2H), 7.10 (s, 1H), 2.76(m, 1H), 2.47 (s, 3H), 1.78- 2.32 (m, 11H) 144 8.86 (d, J = 5.0 Hz, 1H),8.52-8.58 (m, 1H), 8.18-8.32 (m, 3H), 7.83-7.92 (m, 366 2H), 7.40-7.50(m, 1H), 2.81 (m, 1H), 2.80 (s, 3H), 1.78-2.32 (m, 11H) 145 8.54 (d, J =4.0 Hz, 1H), 8.20-8.45 (m, 4H), 8.06 (s, 1H), 7.95 (t, J = 8.0 Hz, 3691H), 7.44-7.60 (m, 2H), 2.76-2.81 (m, 1H), 1.78-2.32 (m, 11H) 146 8.54(d, J = 4.0 Hz, 1H), 8.28 (s, 1H), 7.80-8.20 (m, 5H), 7.42-7.50 (m, 1H),369 7.06-7.12 (m, 1H), 2.75 (m, 1H), 1.78-2.32 (m, 11H) 147 8.54 (d, J =4.0 Hz, 1H), 8.25 (s, 1H), 8.20 (d, J = 7.8 Hz, 1H), 8.10 (s, 1H), 3837.85 (t, J = 8.0 Hz, 1H), 7.20-7.47 (m, 3H), 2.75-2.82 (m, 1H), 2.56 (s,3H), 1.78-2.32 (m, 11H) 148 8.54 (d, J = 4.0 Hz, 1H), 8.25 (s, 1H), 8.20(d, J = 8.0 Hz, 1H), 8.0 (s, 1H), 418 7.40-7.98 (m, 5H), 6.25 (s, 1H),2.80 (m, 1H), 1.78-2.40 (m, 11H) 149 8.54 (d, J = 4.0 Hz, 1H), 8.24 (s,1H), 8.20 (d, J = 8.0 Hz, 1H), 7.40-8.05 (m, 375 6H), 6.25 (s, 1H),2.75-2.80 (m, 1H), 1.78-2.40 (m, 11H) 150 8.54 (d, J = 4.0 Hz, 1H), 8.25(s, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.89 (t, J = 393 7.8 Hz, 1H), 7.80(s, 1H), 7.42-7.78 (m, 3H), 6.20 (s, 1H), 2.80 (m, 1H), 1.78-2.40 (m,11H) 151 9.18 (s, 1H), 8.61 (s, 1H), 8.00 (s, 1H), 7.75-7.80 (m, 1H),7.07-7.20 (m, 401 2H), 6.81-6.90 (m, 1H), 2.75 (m, 1H), 2.63 (s, 3H),1.78-2.32 (m, 11H) 152 9.20 (s, 1H), 8.72 (s, 1H), 7.95-8.11 (m, 3H),7.76 (s, 1H), 7.08-7.12 (m, 384 1H), 2.80 (m, 1H), 2.63 (s, 3H),1.78-2.32 (m, 11H) 153 9.20 (s, 1H), 8.73 (s, 1H), 8.00 (s, 1H), 7.82(s, 1H), 7.70-7.75 (m, 1H), 7.48- 408 7.54 (m, 1H), 6.20 (s, 1H), 2.80(m, 1H), 2.63 (s, 3H), 1.78-2.40 (m, 11H) 154 9.17 (s, 1H), 8.59 (s,1H), 8.36 (d, J = 3.0 Hz, 1H), 8.18-8.21 (m, 1H), 8.04 384 (s, 1H), 8.00(s, 1H), 7.50-7.54 (m, 1H), 2.76-2.79 (m, 1H), 2.59 (s, 3H), 1.78-2.32(m, 11H) 155 9.16 (s, 1H), 8.60 (s, 1H), 8.25-8.30 (m, 1H), 8.00 (s,1H), 7.80 (s, 1H), 7.26- 402 7.35 (m, 1H), 2.80 (m, 1H), 2.60 (s, 3H),1.78-2.32 (m, 11H) 156 9.18 (s, 1H), 8.85 (d, J = 5.1 Hz, 1H), 8.60 (s,1H), 8.19 (s, 1H), 8.00 (s, 1H), 381 7.88 (d, J = 5.0 Hz, 1H), 2.77-2.83(m, 1H), 2.77 (s, 3H), 2.60 (s, 3H), 1.78- 2.32 (m, 11H). 157 9.18 (s,1H), 8.85 (d, J = 5.1 Hz, 1H), 8.60 (s, 1H), 8.19 (s, 1H), 8.00 (s, 1H),381 7.88 (d, J = 5.0 Hz, 1H), 2.77-2.83 (m, 1H), 2.77 (s, 3H), 2.60 (s,3H), 1.78- 2.32 (m, 11H). 158 9.17 (s, 1H), 8.57 (s, 1H), 8.51-8.54 (m,1H), 8.23 (s, 1H), 8.15-8.19 (m, 366 1H), 8.01 (s, 1H), 7.82-7.87 (m,1H), 7.39-7.44 (m, 1H), 2.77-2.82 (m, 1H), 2.60 (s, 3H), 1.78-2.32 (m,11H). 159 9.17 (s, 1H), 8.57 (s, 1H), 8.51-8.54 (m, 1H), 8.23 (s, 1H),8.15-8.19 (m, 366 1H), 8.01 (s, 1H), 7.82-7.87 (m, 1H), 7.39-7.44 (m,1H), 2.77-2.82 (m, 1H), 2.60 (s, 3H), 1.78-2.32 (m, 11H). 160 9.17 (s,1H), 8.60 (s, 1H), 7.99 (s, 1H), 7.36-7.49 (m, 3H), 7.15-7.22 (m, 3831H), 6.18 (s, 1H), 2.73-2.78 (m, 1H), 2.60 (s, 3H), 1.78-2.32(m, 11H).161 9.17 (s, 1H), 8.60 (s, 1H), 7.99 (s, 1H), 7.36-7.49 (m, 3H),7.15-7.22 (m, 383 1H), 6.18 (s, 1H), 2.73-2.78 (m, 1H), 2.60 (s, 3H),1.78-2.32 (m, 11H), 162 9.39 (d, J = 2.0 Hz, 1H), 8.75 (d, J = 2.5 Hz,1H), 8.47-8.51 (m, 1H), 7.95 (s, 385 1H), 7.72 (t, J = 2.0 Hz, 1H),7.58-7.63 (m, 1H), 7.42-7.50 (m, 1H), 7.32-7.40 (m, 1H), 6.20 (s, 1H),2.75 (m, 1H), 1.78-2.32 (m, 11H) 163 9.39 (d, J = 2.0 Hz, 1H), 8.75 (d,J = 2.5 Hz, 1H), 8.47-8.51 (m, 1H), 7.95 (s, 385 1H), 7.72 (t, J = 2.0Hz, 1H), 7.58-7.63 (m, 1H), 7.42-7.50 (m, 1H), 7.32-7.40 (m, 1H), 6.20(s, 1H), 2.75 (m, 1H), 1.78-2.32 (m, 11H) 164 9.18 (s, 1H), 8.61 (s,1H), 8.24 (m, 2H), 8.02 (s, 1H), 7.95 (s, 1H), 7.72-7.69 366 (m, 1H),7.04 (s, 1H), 2.61 (s, 3H), 2.58-2.56 (m, 1H), 2.30-2.05 (m, 5H),1.91-1.73 (m, 6H) 165 9.34 (s, 1H), 9.17 (s, 1H), 8.61 (s, 1H), 8.21 (s,1H) 8.01 (s, 1H), 7.83 (s, 381 1H), 2.60-2.54 (m, 4H), 2.45 (s, 3H),2.30-2.20 (m, 3H), 2.11-2.07 (m, 2H), 1.96-1.73 (m, 6H) 166 9.10 (s,1H), 8.54 (s, 1H), 8.46 (d, J = 5.5 Hz, 1H), 7.93-7.90 (m, 2H), 7.84 381(s, 1H), 2.53-2.50 (m, 7H), 2.18-1.65 (m, 11H) 167 9.17 (s, 1H), 8.79(m, 1H), 8.61 (s, 1H), 7.97 (s, 1H), 6.52 (d, J = 1.0 Hz, 386 1H),2.60-2.57 (m, 4H), 2.34 (s, 3H), 2.28-2.21 (m, 3H), 2.11-2.01 (m, 2H),1.93-1.75 (m, 5H), 1.73-1.70 (m, 1H) 168 9.26 (m, 1H), 9.17 (s, 1H),8.61 (s, 1H), 7.98 (s, 1H), 7.46 (d, J = 3.5 Hz, 372 1H), 6.98 (d, J =3.5 Hz, 1H), 2.61-2.57 (m, 4H), 2.31-2.20 (m, 3H), 2.11- 2.04 (m, 2H),1.92-1.71 (m, 6H) 169 8.33 (s, 1H), 8.00-7.79 (m, 3H), 7.74-7.71 (m,1H), 7.60-7.57 (m, 1H), 7.28- 379 7.27 (m, 1H), 6.90 (d, J = 7.5 Hz,1H), 2.58 (m, 4H), 2.43 (s, 3H), 2.24-2.00 (m, 5H), 1.91-1.84 (m, 6H)170 8.86 (d, J = 7.5 Hz, 1H), 8.21 (s, 1H), 8.02 (d, J = 10.0 Hz, 1H),7.92-7.88 380 (m, 2H), 7.58 (m, 1H), 6.89 (d, J = 7.5 Hz, 1H), 2.78 (s,3H), 2.58-2.55 (m, 1H), 2.43 (s, 3H), 2.24-2.05 (m, 6H), 1.91-1.84 (m,5H) 171 8.02 (d, J = 7.5 Hz, 1H), 7.86 (s, 1H), 7.58-7.56 (m, 1H), 7.36(s, 1H), 7.09 385 (s, 1H), 6.89 (d, J = 7.5 Hz, 1H), 2.56-2.54 (m, 1H),2.46 (s, 3H), 2.44 (s, 3H), 2.27-2.05 (m, 5H), 1.92-1.84 (m, 6H) 1728.02 (d, J = 7.5 Hz, 1H), 7.88-7.86 (m, 2H), 7.57-7.64 (m, 2H), 7.42 (s,1H), 371 6.89 (d, J = 7.5 Hz, 1H), 2.58-2.57 (m, 1H), 2.43 (s, 3H),2.24-2.05 (m, 5H), 1.91-1.84 (m, 6H) 173 9.25 (d, J = 7.5 Hz, 1H), 8.36(s, 1H), 8.03-7.88 (m, 3H), 7.60-7.56 (m, 1H), 380 6.89 (d, J = 7.5 Hz,1H), 2.65 (s, 3H), 2.58-2.57 (m, 1H), 2.43 (s, 3H), 2.24- 2.05 (m, 5H),1.91-1.77(m, 6H) 174 9.40 (d, J = 7.5 Hz, 1H), 8.75 (s, 1H), 8.52 (s,1H), 8.03-7.86 (m, 3H), 7.60- 366 7.56 (m, 1H), 6.89 (d, J = 7.5 Hz,1H), 2.58 (m, 1H), 2.43 (s, 3H), 2.24-2.05 (m, 5H), 1.91-1.77(m, 6H) 1758.04-8.03 (m, 2H), 7.61-7.50 (m, 3H), 7.32-7.27 (m, 2H), 6.90 (d, J =7.5 Hz, 378 1H), 6.22 (s, 1H), 2.53 (m, 1H), 2.46 (s, 3H), 2.42 (s, 3H),2.14-1.88 (m, 5H), 1.86-1.72 (m, 6H) 176 8.01 (d, J = 7.5 Hz, 1H), 7.90(s, 1H), 7.71-7.70 (m, 1H), 7.60-7.57 (m, 2H), 398 7.46-7.45 (m, 1H),7.37-7.34 (m, 1H), 6.89 (d, J = 7.0 Hz, 1H), 6.25 (s, 1H), 2.51-2.49 (m,1H), 2.44 (s, 3H), 2.24-2.00 (m, 5H), 1.89-1.82(m, 6H) 177 8.53 (d, J =7.5 Hz, 1H), 8.25 (s, 1H), 8.17-8.16 (m, 1H), 8.03-8.01 (m, 1H), 3657.92 (s, 1H), 7.84-7.82 (m, 1H), 7.58-7.55 (m, 1H), 7.42-7.40 (m, 1H),6.88- 6.87 (m, 1H), 2.60 (m, 1H), 2.43 (s, 3H), 2.24-2.00 (m, 5H),1.89-1.76 (m, 6H) 178 8.53 (d, J = 6.0 Hz, 1H), 8.31 (s, 1H), 8.05-7.74(m, 3H), 7.73 (t, J = 8.0 Hz, 380 1H), 7.29-7.27 (m, 1H), 2.64-2.57 (m,7H), 2.27-1.72 (m, 11H) 179 8.87 (d, J = 5.0 Hz, 1H), 8.54 (d, J = 5.5Hz, 1H), 8.20 (s, 1H), 7.99 (d, J = 381 5.5 Hz, 1H), 7.89 (d, J = 5.0Hz, 1H), 2.79 (s, 3H), 2.61 (d, J = 5.0 Hz, 3H), 2.58 (s, 1H), 2.23 (d,J = 6.0 Hz, 3H), 2.08-2.06(m, 2H), 1.93-1.81 (m, 7H) 180 8.54 (d, J =6.0 Hz, 1H), 7.98 (d, J = 6.0 Hz, 1H), 7.89 (s, 1H), 7.37 (s, 1H), 3867.12 (d, J = 1.5 Hz, 1H), 2.62-2.48(m, 7H), 2.25-1.73 (m, 11H) 181 8.53(d, J = 7.5 Hz, 1H), 8.00-7.95 (m, 2H), 7.56-7.53 (m, 2H), 7.32-7.30 (m,379 2H), 6.21 (s, 1H), 2.60 (s, 3H), 2.58 (m, 1H), 2.55 (s, 3H),2.24-2.05 (m, 5H), 1.91-1.71 (m, 6H) 182 8.53 (d, J = 7.5 Hz, 1H),7.98-7.95 (m, 2H), 7.71-7.63 (m, 2H), 7.48-7.36 (m, 399 2H), 6.21 (s,1H), 2.60 (s, 3H), 2.58 (m, 1H), 2.24-2.05 (m, 5H), 1.91-1.71 (m, 6H)183 9.31 (s, 1H), 8.32 (s, 1H), 8.22 (s, 1H), 7.98 (d, J = 7.5 Hz, 1H),7.88 (s, 1H), 380 7.74-7.71 (m, 1H), 7.28-7.27 (m, 1H), 2.64-2.62 (m,1H), 2.61 (s, 3H), 2.46 (s, 3H), 2.27-1.75 (m, 11H) 184 9.35 (s, 1H),8.22 (s, 1H), 7.72 (s, 1H), 7.38 (s, 1H), 7.12 (s, 1H), 2.61-2.58 386(m, 1H), 2.48 (s, 3H), 2.47 (s, 3H), 2.25-1.88 (m, 11H) 185 9.35 (s,1H), 8.23 (s, 1H), 7.79 (s, 1H), 7.72 (s, 1H), 7.61 (d, J = 6.5 Hz, 1H),399 7.48 (d, J = 8.0 Hz, 1H), 7.38 (t, J = 8.0 Hz, 1H), 6.18 (s, 1H),2.57-2.54 (m, 1H), 2.47 (s, 3H), 2.29-1.75 (m, 11H) 186 9.49 (s, 1H),8.82 (s, 1H), 8.45 (s, 1H), 8.25 (s, 1H), 8.07 (d, J = 8.0 Hz, 384 1H),7.89 (s, 1H), 7.80 (d, J = 3.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.49-7.46 (m, 1H), 7.33-7.32 (m, 1H), 2.26-1.65 (m, 12H) 187 9.57 (s, 1H),8.35 (s, 1H), 8.24 (s, 1H), 7.89 (s, 1H), 7.55 (s, 1H), 7.51-7.49 385(m, 1H), 7.33-7.30 (m, 2H), 6.20 (s, 1H), 2.57-2.55 (m, 1H), 2.39 (s,3H), 2.31-1.71 (m, 11H)

4. Pharmacological Evaluation of Compounds of the Invention

Compounds of the present invention have been tested in vitro and invivo, and can be tested in vitro and in vivo, in the assays as describedbelow.

In vitro Assays

Radioligand Binding Assays

Binding assays were performed as described in [J. A. O'Brien et al. Mol.Pharmacol., 2003, 64, 731-740] with slight modifications, including thata radioligand that binds to the methyl-5-(2-pyridinylethynyl)pyridine(MPEP) binding site was used in place of [³H]-MPEP. Briefly, afterthawing, the membrane homogenates were resuspended in 50 mM Tris-HCl and0.9% NaCl binding buffer at pH 7.4 to a final assay concentration of 20μg is protein/well for radioligand filtration binding. Incubationsincluded 5 nM radioligand, membranes and either buffer or varyingconcentrations of compound. Samples were incubated for 60 min at roomtemperature with shaking. Non-specific binding was defined with 10 μMcold MPEP when using the radioligand. After incubation, samples werefiltered over a GF/C filter (presoaked in 0.25% polyethyleneimine (PEI))and then washed 4 times using a Tomtec® Harvester 96® Mach III cellharvester (Tomtec, Hamden, Conn.) with 0.5 mL ice-cold 50 mM Tris-HCl(pH 7.4). IC₅₀ values were derived from the inhibition curve and Kivalues were calculated according to the Cheng and Prusoff equation ofKi=IC₅₀/(1+[L]/Kd) described in [Y. Cheng and W. H. Prusoff Biochem.Pharmacol. 1973, 22, 3099-3108] where [L] is the concentration ofradioligand and Kd is its dissociation constant at the receptor, derivedfrom the saturation isotherm. The Ki values of compounds of theinvention were <10 μM. The Ki values of representative compounds werelisted in Table 4.

Calcium Mobilization Assay to Test for Negative or Positive AllostericActivity

The cDNA for rat metabotropic glutamate receptor 5 (rmGluR5) and thecDNA for human metabotropic glutamate receptor 5 (rmGluR5) were generousgifts from S. Nakanishi (Kyoto University, Kyoto, Japan). The rmGluR5 orrmGluR5 was stably expressed in a HEK 293 cell line and grown inDulbecco's Modified Eagle Medium (DMEM) (Invitrogen, Carlsbad, Calif.)with supplements (10% bovine calf serum, 4 mM glutamine, 100 units/mLpenicillin, 100 μg/mL streptomycin and 0.75 mM G1418) at 37° C., 5% CO₂.Twenty-four hours prior to assay, cells were seeded into 384-well blackwall microtiter plates coated with poly-D-lysine. Just prior to assay,media was aspirated and cells dye-loaded (25 μL/well) with 3 μMFluo-4/0.01% pluronic acid in assay buffer (Hank's Balanced SalineSolution (HBSS)): 150 mM NaCl, 5 mM KCl, 1 mM CaCl₂, 1 mM MgCl₂, plus 20mM N-2-Hydroxyethylpiperazine-N′-2-ethanesulfonic acid (HEPES), pH 7.4,0.1% bovine serum albumin (BSA) and 2.5 mM probenicid) for 1 hour in 5%CO₂ at 37° C. After excess dye was discarded, cells were washed in assaybuffer and layered with a final volume equal to 30 μL/well. Basalfluorescence is monitored in a fluorometric imaging plate reader (FLIPR)(Molecular Devices, Sunnyvale, Calif.) with an excitation wavelength of488 nm and an emission range of 500 to 560 nm. Laser excitation energywas adjusted so that basal fluorescence readings were approximately10,000 relative fluorescent units. Cells were stimulated with an EC₂₀ oran EC₈₀ concentration of glutamate in the presence of a compound to betested, both diluted in assay buffer, and relative fluorescent unitswere measured at defined intervals (exposure=0.6 sec) over a 3 minperiod at room temperature. Basal readings derived from negativecontrols were subtracted from all samples. Maximum change influorescence was calculated for each well. Concentration-response curvesderived from the maximum change in fluorescence were analyzed bynonlinear regression (Hill equation). A negative modulator can beidentified from these concentration-response curves if a compoundproduces a concentration dependent inhibition of the EC₈₀ glutamateresponse. Representative Examples were tested in the above assay usinghmGluR5, and FLIPR maximum inhibition ranged from about 70% to about100%, while FLIPR IC₅₀ ranged from about 0.32 nM to about 1 μM. The IC₅₀values of representative compounds were listed in Table 4.

A positive modulator (PAM) can be identified from theseconcentration-response curves if a compound produces a concentrationdependent increase in the EC₂₀ glutamate response. A silent allostericmodulator (SAM) can be identified based on results from both theradioligand assay and the calcium mobilization assay. If a compoundactively binds to an allosteric site of the receptor based on theradioligand assay, but has no measurable intrinsic efficacy in thecalcium mobilization assay, the compound is a SAM.

TABLE 4 In vitro activity of representative compounds Example hmGluR5hmGluR5 hmGlu5 FLIPR % No. Ki (nM) FLIPR IC₅₀ (nM) inhibition 2 27 3.789 6 78 9 92 15 340 26 88 36 280 35 87 126 39 0.32 86 160 35 3.9 89 1611200 134 90 171 65 4.7 94 176 500 33 91 178 370 38 90

In Viva Assays

Compounds of formula (I) can be tested for in vivo anxiolytic effect ina mouse marble burying (mMB) assay similar to that described in [K.Njung'e, K. and S. L. Handley, Pharmacology Biochemistry and Behavior,1991, 38, 63-67].

Anxiolytic effect in vivo can also be tested via a modifiedGeller-Seifter conflict test described in [N. A. Moore et al.Behavioural Pharmacology. 1994, 5, 196-202].

The “Vogel Conflict Test” as described by Vogel et al.[Psychopharmacologia, 1971, 21, 1-7] also can be used to detectanxiolytic activity of a compound of formula (I) because anxiolyticsincrease punished drinking.

Compounds of the invention also can be evaluated in vivo for anxiolyticeffects using a light-enhanced startle (LES) reflex method as thatdescribed in [Walker and Davis. Biol. Psychiatry, 1997, 42, 461-471].

Anxiolytic-like properties also can be evaluated using these additionaltests: (1) social interaction described in [S. E. File and P. SethEuropean Journal of Pharmacology, 2003. 463, 35-53], and (2) elevatedplus-maze described in [S. M. Korte and S. F. De Boer European Journalof Pharmacology, 2003, 463, 163-175].

Compounds of formula (I) can be evaluated in vivo for antidepressiveeffects. An assessment of depression-like actions can be measured usinga forced swim test similar to that described in [J. F. Cryan, et al.Neuroscience and Biobehavioral Reviews 2005, 29, 547-569.]

Antidepressive effect also can be evaluated using the Flinders SensitiveLine (FSL) rat in the FST and social interaction test as described in[D. H. Overstreet and G. Griebel Pharmacol Biochem Behav., 2005, 82, 1:223-227].

Anxiolytic and antidepressive effects also can be evaluated using aparadigm for decreased HPA axis feedback (David et al., 2007, SFNmeeting in San Diego). This model based on the chronic delivery ofcorticosterone in the drinking water, causes anxiety- anddepression-like behaviors in mice.

Parkinson's disease (PD) can be assessed by measuring the neurotoxicityof MPTP in rats as described in [E. H. Lee et al. Chin. J. Physiol.,1992, 35, 4: 317-36]. Also, experimentally induced striatal DA depletionin animals is a valid model of Parkinsonism, as described in [W. SchultzProg. Neurobiol., 1982, 18, 2-3: 121-66]. The capacity of certainsubstances to damage catecholaminergic neurons has been used extensivelyto produce DA deficiency in animals, as described in [L. E. Annett etal. Exp. Neurol., 1994, 125, 2: 228-46]. PD can also be assessed bymeasuring the neurotoxicity induced by 6-hydroxydopamine (6-OHDA) asdescribed in [N. Breysse et al. J. Neurosci., 2002, 22, 13: 5669-5678;D. Rylander et al. J. Pharmacol. Exp. Ther., 2009, 330, 1: 227-235; andL. Chen et al., “Chronic, systemic treatment with a metabotropicglutamate receptor 5 antagonist in 6-hydroxydopamine partially lesionedrats reverses abnormal firing of dopaminergic neurons,” Brain Res.,2009, 1286, 192-200].

Fragile X Syndrome can be assessed using the fmrl^(imlCgr) mouse modelas described in [Q. J. Yan et al. Neuropharmacol., 2005, 49, 1053-1066],as well as the Fmrl knockout mice with a selective reduction in mGluR5expression as described in [G. Dölen et al. Neuron, 2007, 56, 955-962].

Preclinically, animals also can be evaluated for blockade/attenuation ofsymptoms associated with schizophrenia. Positive symptoms in animalmodels of schizophrenia can be evaluated by measuring changes in theoverall level of activity of dopamine (DA) activity with concomitantparallel changes in locomotor activity as described in [R. Depoortere etal. Neuropsychopharmacology, 2003, 28, 11: 1889-902], D-amphetamine(AMPH) and phencyclidine (PCP) via induction of model psychosis orlocomotor hyperactivity as described in [W. J. Freed et al.Neuropharmacology, 1984, 23, 2A: 175-81; F. Sams-DoddNeuropsychopharmacology, 1998 19, 1: 18-25]. For example, Depoortere etal., 2003, have described tests for evaluating locomotor activity,catalepsy, climbing and stereotypy, which relate to positivesymptomology and side effect profile, by characterizing compounds withtypical and atypical antipsychotic efficacy. Attenuation inapomorphine-induced climbing, stereotypy and catalepsy (AIC) can beevaluated as described in [Y. K. Fung et al. Pharmacol. Biochem. Behav.,1986, 24, 1: 139-41 and Y. K. Fung et al. Steroids, 1987, 49, 4-5:287-94]. Additionally, negative symptoms of schizophrenia can beevaluated by measuring social interaction under the influence of NMDAantagonists such as PCP, as described in F. Sams-Dodd, 1998, supra.

Cognitive symptoms of memory, including those from Alzheimer's disease,can be evaluated by such models as the Fear Conditioning Paradigmdescribed in [T. J. Gould et al. Behav. Pharmacol., 2002, 13, 4: 287-94,and A. O. Hamm et al. Brain, 2003, 126, Pt 2: 267-75] and the Radial ArmTest described in [J. P. Aggleton et al. Behav. Brain Res., 1996, 19, 2:133-46], while spatial reference memory and learning can be evaluated inthe Morris watermaze test as described in [Morris. Learn. Motiv., 1981,12, 239-260; B. Bontempi et al. Eur. J. Neurosci. 1996, 8, 11: 2348-60].

Additionally, with respect to cognition, memory and hippocampalhypo-functioning can be assessed by measuring the restoration ofsynaptic plasticity in ovariectomized (OVX) female rats as described in[M. Day and M. Good Neurobiol. Learn. Mem., 2005, 83, 1: 13-21].Further, changes in attention function because of schizophrenia can beexamined by the Five (5) Choice Serial Reaction Time Test (5CSRT)described in [J. L. Muir et al. Psychopharmacology (Berl), 1995, 118, 1:82-92 and Robbins et al. Ann. N.Y. Acad. Sci., 1998, 846, 222-37].

Human patients can be evaluated for cognitive diseases or disorders byany of the tests within the skill of those in the art.

Analgesic activity can be evaluated by neuropathic pain model (the“Chung model”) as described in [Kim and Chung, Pain, 1992, 50, 355-363].Analgesic/anti-inflammatory activity can be evaluated in vivo using theFormalin Paw Test in the mouse such as that described by [Wheeler-Acetoet al, Psychopharmacology, 1991, 104, 35-44).

Multiple sclerosis can be evaluated by the experimental autoimmuneencephalomyelitis (EAE) model described in [H. Y. Liu et al. J.Neurosci. Res., 2002, 70, 2: 238-48].

Those skilled in the art will recognize that various changes and/ormodifications may be made to aspects or embodiments of this inventionand that such changes and/or modifications may be made without departingfrom the spirit of this invention. Therefore, it is intended that theappended claims cover all such equivalent variations as will fall withinthe spirit and scope of this invention.

Each reference cited in the present application, including literaturereferences, books, patents and patent applications, is incorporatedherein by reference in its entirety.

1. A compound having the formula (I):

wherein: L is —NHCO— or —CONH—; and R¹ and R² are each independentlyalkyl, cycloalkyl, ketocycloalkyl, heterocyclyl, aryl or heteroaryl,which is optionally mono-, di-, or tri-substituted independently withalkyl, alkoxy, halogen, cyano, nitro, trifluoroalkyl, amino, alkylamino,dialkylamino, acyl, aryl, heteroaryl, heterocyclyl, heterocyclyl-R³,—NHR³, —N(alkyl)R³, —C(O)NHR³, —C(O)N(alkyl)R³, —NHC(O)R³,—N(alkyl)C(O)R³, —OH or —OR³, wherein: R³ is C₁-C₆alkyl orC₁-C₆cycloalkyl, which is optionally substituted with halogen, —CN,—NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, C₁-C₃alkylheterocyclyl,C₁-C₃alkylcarbamate, —C(O)NH(C₁-C₃alkyl), —C(O)N(C₁-C₃alkyl)₂,—NHC(O)—C₁-C₃alkyl, —N(C₁-C₃alkyl)-C(O)—C₁-C₃alkyl, OH, or—O—C₁-C₆alkyl; or a pharmaceutically acceptable salt thereof.
 2. Thecompound of claim 1 wherein R¹ and R² are each independently aryl orheteroaryl, which is optionally mono-, di-, or tri-substitutedindependently with alkyl, alkoxy, halogen, cyano, nitro, trifluoroalkyl,amino, alkylamino, dialkylamino, acyl, —OH or —OR³; and wherein R³ isC₁-C₆alkyl.
 3. The compound of claim 1 or 2 wherein the heteroaryl isselected from the group consisting of optionally mono-, di-, ortri-substituted pyridinyl, pyridazinyl, triazinyl, pyrrolyl, pyrazolyl,imidazolyl, (1,2,3,)- and (1,2,4)-triazolyl, pyrazinyl, pyrimidinyl,tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl,2-quinolinyl, 2-quinazolinyl and 3-phenyl-2-quinolinyl.
 4. The compoundof claim 1 wherein L is —NHCO—.
 5. The compound of claim 1 wherein L is—CONH—.
 6. The compound of claim 1, wherein R¹ is optionally mono-, di-,or tri-substituted aryl.
 7. The compound of claim 1, wherein R¹ isselected from the group consisting of optionally mono-, di-, ortri-substituted pyridinyl, pyridazinyl or triazinyl.
 8. The compound ofclaim 1, wherein R² is optionally mono-, di-, or tri-substituted aryl.9. The compound of claim 1, wherein R² is selected from the groupconsisting of optionally mono-, di-, or tri-substituted pyridinyl,pyridazinyl or triazinyl.
 10. The compound of claim 1 selected from oneof the examples of 1-50 described in table
 1. 11. The compound of claim1 selected from one of the examples of 51-100 described in table
 1. 12.The compound of claim 1 selected from one of the examples of 101-150described in table
 1. 13. The compound of claim 1 selected from one ofthe examples of 15.1-186 described in table
 1. 14. A pharmaceuticalcomposition comprising a compound of claim 1 and a pharmaceuticallyacceptable carrier.
 15. Use of a compound of claim 1 for the in themanufacture of a medicament for treating a disease or disorder, themethod comprises administering a therapeutically effective amount of atleast one compound of claim 1 or a pharmaceutically acceptable saltthereof, wherein the disease or disorder is a central nervous systemdisease or disorder.
 16. The use of claim 15, wherein the centralnervous system disease or disorder is a cognitive, neurodegenerative,psychiatric or neurological disease or disorder.